Indole derivatives and use thereof

ABSTRACT

The Invention provides indole derivatives of Formula I: 
                         
and pharmaceutically acceptable salts and solvates thereof, wherein R 1e , R 1f , A, X, Y, Z, and W 4  are defined as set forth in the specification. The Invention also provides the use of compounds of Formula I and the pharmaceutically acceptable salts and solvates thereof to treat pain. In certain embodiments, the Compounds of the Invention are effective in treating a disorder responsive to blockade of one or more sodium channels.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/976,089, filed Apr. 7, 2014. The content of the afore-mentionedpatent application is incorporated herein by its entirety.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see TABLE 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, H1) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family TTX Gene Tissue IC₅₀Disease Type Symbol Distribution (nM) Association Indications Na_(v)l.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegen- eration Na_(v)l.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegen- eration Na_(v)l.3 SCN3A CNS15 — Pain Na_(v)l.4 SCN4A Skeletal 25 Myotonia Myotonia muscle Na_(v)l.5SCN5A Heart 2,000 Arrhythmia Arrhythmia muscle Na_(v)l.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)l.7 SCN9A PNS 25 Erythermal- Pain giaNa_(v)l.8 SCN10A PNS 50,000 — Pain Na_(v)l.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows 90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc. Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeister and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the Invention provides indole derivatives represented byFormulae I-VIII, provided infra., and pharmaceutically acceptable saltsand solvates thereof, collectively referred to herein as “Compounds ofthe Invention.”

In another aspect, the Invention provides the use of Compounds of theInvention to treat pain. Without wishing to be bound by any theory,Compounds of the Invention can act as blockers of one or more sodium(Na⁺) channels.

In another aspect, the Invention provides compounds as syntheticintermediates that can be used to prepare blockers of one or more sodium(Na⁺) channels.

In still another aspect, the Invention provides a method for treating adisorder responsive to blockade of one or more sodium channels in amammal, comprising administering to the mammal an effective amount of aCompound of the Disclosure.

Further, the Invention provides a method for treating pain (e.g., acutepain, chronic pain, which includes but is not limited to, neuropathicpain, postoperative pain, and inflammatory pain, or surgical pain),comprising administering an effective amount of a Compound of theInvention to a mammal in need of such treatment. In certain embodiments,the Invention provides a method for preemptive or palliative treatmentof pain by administering an effective amount of a Compound of theInvention to a mammal in need of such treatment.

Still further, the Invention provides a method for treating stroke,neuronal damage resulting from head trauma, epilepsy, seizures, generalepilepsy with febrile seizures, severe myoclonic epilepsy in infancy,neuronal loss following global and focal ischemia, migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, dystonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia, comprising administering an effective amountof a Compound of the Invention to a mammal in need of such treatment.

A further aspect of the Invention provides a pharmaceutical compositioncomprising a Compound of the Invention and one or more pharmaceuticallyacceptable carriers.

In another aspect, the Invention provides a pharmaceutical compositionfor treating a disorder responsive to blockade of sodium ion channels,wherein the pharmaceutical composition comprises an effective amount ofa Compound of the Invention in a mixture with one or morepharmaceutically acceptable carriers.

In another aspect, the Invention provides a method of modulating sodiumchannels in a mammal, comprising administering to the mammal aneffective amount of at least one Compound of the Invention.

In another aspect, the Invention also provides Compounds of theInvention for use in treating pain in a mammal, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

In another aspect, the Invention provides Compounds of the Invention foruse in treating stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

The Invention further provides a radiolabeled Compound of the Inventionand the use of such compounds as radioligands in any appropriatelyselected competitive binding assays and screening methodologies. Thus,the Invention further provides a method for screening a candidatecompound for its ability to bind to a sodium channel or sodium channelsubunit using a radiolabeled Compound of the Invention. In certainembodiments, the compound is radiolabeled with ³H, ¹¹C, or ¹⁴C. Thiscompetitive binding assay can be conducted using any appropriatelyselected methodology. In one embodiment, the screening method comprises:i) introducing a fixed concentration of the radiolabeled compound to anin vitro preparation comprising a soluble or membrane-associated sodiumchannel, subunit or fragment under conditions that permit theradiolabeled compound to bind to the channel, subunit or fragment,respectively, to form a conjugate; ii) titrating the conjugate with acandidate compound; and iii) determining the ability of the candidatecompound to displace the radiolabeled compound from said channel,subunit or fragment.

In another aspect, the Invention provides a Compound of the Inventionfor use in the manufacture of a medicament for treating pain in amammal. In one embodiment, the Invention provides the use of a Compoundof the Invention in the manufacture of a medicament for palliative orpreemptive treatment of pain, such as acute pain, chronic pain, orsurgical pain.

Still further, the Invention provides a Compound of the Invention foruse in the manufacture of a medicament for treating stroke, neuronaldamage resulting from head trauma, epilepsy, seizures, general epilepsywith febrile seizures, severe myoclonic epilepsy in infancy, neuronalloss following global and focal ischemia, migraine, familial primaryerythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy,ataxia, dystonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia, in a mammal.

Additional embodiments and advantages of the Invention will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the Invention. Theembodiments and advantages of the Invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The Invention is based on, in part, the discovery of novel compoundsthat can be used to treat pain. Without wishing to be bound by anytheory, certain Compounds of the Invention act as blockers of sodium(Na⁺) channels while in treating pain. Thus, in certain embodiments, theCompounds of the Invention are useful for treating disorders responsiveto blockade of one or more sodium ion channels.

In one embodiment, Compounds of the Invention are compounds representedby Formula I:

and the pharmaceutically acceptable salts and solvates thereof,wherein:

A is selected from the group consisting of:

W₁ is selected from the group consisting of CR^(1a) and N;

W₂ is selected from the group consisting of CR^(1b) and N;

W₃ is selected from the group consisting of CR^(1c) and N;

with the proviso that at least one of W₁, W₂, and W₃ is N;

W₄ is selected from the group consisting of CR^(1d) and N;

W₅ is selected from the group consisting of —O—, —S—, and —NR^(1g)—;

W₆ is selected from the group consisting of CH and N;

each of R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), and R^(1f),independently, is selected from the group consisting of hydrogen,halogen, alkyl, cyano, haloalkyl, hydroxy, alkoxy, and haloalkoxy;

R^(1g) is selected from the group consisting of hydrogen and alkyl; G isselected from the group consisting of dihydroxyalkyl,—(CHR^(1h))_(m)—S(═O)₂E, and —(CHR^(1h))_(m)—C(═O)E;

m is 0, 1, or 2;

each R^(1b) is independently selected from the group consisting ofhydrogen and hydroxy;

E is selected from the group consisting of hydroxy, alkoxy,hydroxyalkyl, and —NR¹R²;

R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclo, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substituted(cycloalkyl)alkyl, optionally substituted (heterocyclo)alkyl, optionallysubstituted (hetero aryl)alkyl, (amino)alkyl, (alkyl amino)alkyl,(dialkylamino)alkyl, (carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl,hydroxyalkyl, and heteroalkyl;

R² is selected from the group consisting of hydrogen, alkyl, andoptionally substituted aryl; or

R¹ and R² taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

X is selected from the group consisting of NR^(4a), O and S; Y isCR^(3a); and Z is CR^(3b); or

X is CR^(3b); Y is CR^(3a); and Z is selected from the group consistingof NR^(4a), O, and S; or

X is NR^(4b), Y is N, and Z is CR^(3c); or

X is N, Y is NR^(4b), and Z is CR^(3c); or

X is N, Y is CR^(3d), and Z is NR^(4c); or

X is NR^(4c), Y is CR^(3d), and Z is N;

R^(3a) is selected from the group consisting of hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl;

R^(3b) is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,optionally substituted aryl, (heterocycloamino)alkyl, —CO₂H, and—C(═O)NR^(12a)R^(12b);

R^(3c) is selected from the group consisting of hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl;

R^(3d) is selected from the group consisting of hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl;

R^(4a) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, hydroxyalkyl, optionally-substituted (cycloalkyl)alkyl,optionally-substituted (heterocyclo)alkyl, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, optionally-substituted aralkyl,optionally-substituted (heteroaryl)alkyl, optionally substituted aryl,—COR^(11a), and —SO₂R^(11b);

R^(4b) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, hydroxyalkyl, optionally-substituted (cycloalkyl)alkyl,(amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,optionally-substituted aralkyl, optionally substituted(heteroaryl)alkyl, and optionally-substituted aryl,

R^(4c) is selected from the group consisting of hydrogen, alkyl,optionally substituted-aralkyl, optionally-substituted cycloalkyl,optionally-substituted aryl, and optionally-substituted heteroaryl;

R^(11a) is selected from the group consisting of alkyl,optionally-substituted cycloalkyl, optionally-substituted aryl, andoptionally-substituted heteroaryl;

R^(11b) is selected from the group consisting of alkyl,optionally-substituted cycloalkyl, optionally-substituted aryl,optionally-substituted heteroaryl, amino, alkylamino, dialkylamino, andheterocyclo;

R^(12a) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, heterocyclo, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted aralkyl,optionally-substituted (cycloalkyl)alkyl, optionally-substituted(heterocyclo)alkyl, optionally-substituted (hetero aryl)alkyl,(amino)alkyl, (alkyl amino)alkyl, (dialkylamino)alkyl,(carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl, hydroxyalkyl, andheteroalkyl;

R^(12b) is selected from the group consisting of hydrogen and alkyl; or

R^(12a) and R^(12b) taken together with the nitrogen atom to which theyare attached form an optionally substituted 3- to 8-membered heterocyclogroup;

R⁵ is selected from the group consisting of hydrogen, halo, hydroxy,alkyl, hydroxyalkyl, cyano, heterocyclo, and —X¹—R⁷;

X¹ is selected from the group consisting of —O—, —NR^(8a)—, and—(CH₂)_(t)—Y¹—;

Y¹ is selected from the group consisting of —O— and —NR^(8b)—;

t is 1 or 2;

R⁷ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl,

R^(8a) is selected from the group consisting of hydrogen and alkyl;

R^(8b) is selected from the group consisting of hydrogen and alkyl; or

R^(8b) and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R⁹ is selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl; and

R^(10a) and R^(10b) are independently selected from the group consistingof hydrogen and alkyl; or

R^(10a) and R^(10b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally-substituted heterocyclo.

In one embodiment of Formula I, when A is

R⁵ is —X¹—R⁷, and X¹ is —(CH₂)_(t)—Y¹—, then Y¹ is directly attached toR⁷.

In certain embodiments, Compounds of the Invention are compoundsrepresented by Formula II:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), R⁵, W₁, W₂, W₃, W₄, X, Y, Z, and G are those as definedabove in connection with Formula I.

Another embodiment of the Invention provides compounds represented byFormula III:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), W₄, W₅, W₆, X, Y, Z, and G are those as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), R⁵, W₄, X, Y, Z, and G are those as defined above inconnection with Formula I.

In still another embodiment, Compounds of the Invention are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), R⁵, W₄, X, Y, Z, and G are those as defined above inconnection with Formula I.

In a further embodiment, Compounds of the Invention are compoundsrepresented by Formula VI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), R⁵, W₄, X, Y, Z, and G are those as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), R⁵, W₄, X, Y, Z, and G are those as defined above inconnection with Formula I.

A separate embodiment provides that Compounds of the Invention arecompounds represented by Formula VIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR^(1e), R^(1f), W₄, X, Y, Z, and G are those as defined above inconnection with Formula I.

In one embodiment, Compounds of the Invention are compounds representedby any one of Formulae I-VIII, provided supra., and the pharmaceuticallyacceptable salts and solvates thereof, wherein G is dihydroxyalkyl. Inone embodiment, G is dihydroxyalkyl. For example, G is dihydroxyalkylselected from the group consisting of:

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and pharmaceuticallyacceptable salts and solvates thereof, wherein G is—(CHR^(1h))_(m)—C(═O)E, m is 1 or 2, and each R^(1b) is hydroxy. In oneembodiment, G is —CH(OH)—C(═O)E selected from the group consisting of:

In a separate embodiment, G is —CH(OH)CH(OH)C(═O)E selected from thegroup consisting of:

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein G is—(CHR^(1h))_(m)—C(═O)E and m is 0, i.e., G is —C(═O)E.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein G is—(CHR^(1h))_(m)—S(═O)₂E and m is 0, i.e., G is —S(═O)₂E.

In certain embodiments, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein:

G is selected from the group consisting of —(CHR^(1h))_(m)—S(═O)₂E and—(CHR^(1h))_(m)—C(═O)E;

E is —NR¹R²;

R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted (cycloalkyl)alkyl;

R² is hydrogen; or

R¹ and R² taken together with the nitrogen atom to which they areattached form a 5- or 6-membered optionally substituted heterocyclo.

In one embodiment, E is —NH₂.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(1e) and R^(1f) arehydrogen.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein W₄ is CH.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein, within the compoundstructure:

is selected from the group consisting of:

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein X is NR^(4a) or Z isNR^(4a), and R^(4a) is selected from the group consisting of hydrogen,alkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted(heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, optionally substituted aralkyl, optionallysubstituted (heteroaryl)alkyl, and —SO₂R^(11b).

Further, one embodiment of the Invention provides compounds representedby any one of Formulae I-VIII, and the pharmaceutically acceptable saltsand solvates thereof, wherein R^(3b) is selected from the groupconsisting of hydrogen, optionally substituted aryl,(heterocycloamino)alkyl, and —C(═O)NR^(12a)R^(12b).

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein X is NR^(4b) or Y isNR^(4b), and R^(4b) is selected from the group consisting of hydrogen,alkyl, optionally substituted aryl, and optionally substituted aralkyl.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein X is NR^(4c) or Z isNR^(4c), and R^(4c) is selected from the group consisting of hydrogen,alkyl, and optionally substituted aryl.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-VIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein Y is CR^(3d), and R^(3d)is selected from the group consisting of hydrogen and optionallysubstituted aryl.

Certain embodiments of the Invention provide compounds represented byany one of Formulae I, II, or IV-VII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein A is

and R⁵ is selected from the group consisting of hydrogen, hydroxyalkyl,and —X—R⁷. In one embodiment, R⁵ is hydrogen. In another embodiment, R⁵is hydroxyalkyl. In a separate embodiment, R⁵ is —X¹—R⁷. In oneembodiment, X¹ is —O—. In one embodiment, X¹ is NH—. In one embodiment,X¹ is —CH₂NH—. In one embodiment, X¹ is —CH₂O—.

In certain embodiments, R⁷ is selected from the group consisting of:

In one embodiment, R⁹ is alkyl (e.g., methyl, ethyl, etc.).

In certain embodiments, Compounds of the Invention include compoundspresented in TABLE 2, and the pharmaceutically acceptable salts andsolvates thereof.

TABLE 2 No. Structure Name  29

6-(1H-indol-5-yl)picolinamide  32

6-(1H-indol-5-yl)-N-(4- (trifluoromethyl)phenyl)picolinamide  33

6-(1H-indol-5-yl)-N,N-bis(4- (trifluoromethyl)phenyl)picolinamide  35

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1H-indol-5-yl)pyrimidine-4-carboxamide  36

(S)-2-(1H-indol-5-yl)-6-((2- oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide  37

(S)-2-(1H-indol-5-yl)-6-((2- oxopyrrolidin-3-yl)oxy)pyrimidine-4-carboxamide  41

6-(1-isobutyl-1H-indol-5-yl)-N-(1,2,4- thiadiazol-5-yl)pyridine-2-sulfonamide  42

(S)-2-(2-(2,4-dimethoxyphenyl)-1-(4- fluorophenyl)-1H-benzo[d]imidazol-5-yl)-6-((2-oxopyrrolidin-3- yl)amino)pyrimidine-4-carboxamide  44

(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-1H- benzo[d]imidazol-6-yl)pyrimidine-4-carboxamide  45

(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-1H- benzo[d]imidazol-5-yl)pyrimidine-4-carboxamide  47

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-isobutyl-1H-indol-5-yl)pyrimidine-4-carboxamide  50

(R)-1-(2-(1-(4- (trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4- yl)ethane-1,2-diol  51

(S)-1-(2-(1-(4- (trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4- yl)ethane-1,2-diol  56

6-(1-(4-(trifluoromethyl)benzyl)-1H- indol-5-yl)picolinamide  57

6-(1-((4-(trifluoromethyl)phenyl) sulfonyl)-1H-indol-5-yl)picolinamide 58

6-(1-(cyclohexylmethyl)-1H-indol-5- yl)picolinamide  59

6-(1-(cyclohexylsulfonyl)-1H-indol-5- yl)picolinamide  61

6-(1-(4-fluorobenzyl)-1H-indol-5- yl)picolinamide  62

6-(1-(4-methylbenzyl)-1H-indol-5- yl)picolinamide  63

6-(1-(2-cyclohexylethyl)-1H-indol-5- yl)picolinamide  64

6-(1-(pyridin-4-ylmethyl)-1H-indol-5- yl)picolinamide  65

6-(1-(2-morpholinoethyl)-1H-indol-5- yl)picolinamide  66

6-(1-((3,5-dimethylisoxazol-4- yl)methyl)-1H-indol-5- yl)picolinamide 67

6-(1-isobutyl-1H-indol-5- yl)picolinamide  68

6-(1-((2-methylthiazol-4-yl)methyl)- 1H-indol-5-yl)picolinamide  75

6-(1-methyl-1H-indol-5-yl)-N-(4- (trifluoromethyl)phenyl)picolinamide 76

N-cyclohexyl-6-(1H-indol-5- yl)picolinamide  77

6-(1H-indazol-5-yl)-N-(4- (trifluoromethyl)phenyl)picolinamide  78

(S)-2-(1H-indol-5-yl)-6-((2- oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4- carboxamide  79

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4- carboxamide  80

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4- carboxamide  81

6-(benzofuran-5-yl)-N-(4- (trifluoromethyl)phenyl)picolinamide  83

N-(cyclohexylmethyl)-6-(1H-indol-5- yl)picolinamide  84

(6-(1H-indol-5-yl)pyridin-2- yl)(pyrrolidin-1-yl)methanone  85

N-cyclopentyl-6-(1H-indol-5- yl)picolinamide  86

(6-(1H-indol-5-yl)pyridin-2-yl)(2,6- dimethylmorpholino)methanone  87

6-(1H-indol-5-yl)-N-(1H-tetrazol-5- yl)picolinamide  88

(S)-6-(1H-indol-5-yl)-4-((2- oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)picolinamide 105

6-(1-(4-(trifluoromethyl)benzyl)-1H- indazol-5-yl)picolinamide 106

(S)-1-(6-(1-(4- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-blpyridin-5-yl)pyridin-2- yl)ethane-1,2-diol 107

(S)-1-(6-(1-(4- (trifluoromethyl)benzyl)-1H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diol 108

(S)-1-(6-(2-(4- (trifluoromethyl)benzyl)-2H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diol 109

(S)-1-(6-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)pyridin-2-yl)ethane-1,2-diol 110

(S)-1-(6-(1-(4- (trifluoromethyl)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2- yl)ethane-1,2-diol 111

(S)-1-(6-(1-(piperidin-1-ylsulfonyl)-1H-indol-5-yl)pyridin-2-yl)ethane-1,2- diol 112

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5- yl)pyrimidine-4-carboxamide 113

(S)-6-((1-amino-1-oxopropan-2- yl)amino)-2-(1-(cyclohexylmethyl)-1H-indol-5-yl)pyrimidine-4- carboxamide 119

(R)-4-(1,2-dihydroxyethyl)-6-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)picolinonitrile 120

(R)-4-(1,2-dihydroxyethyl)-6-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide 121

(S)-4-(1,2-dihydroxyethyl)-6-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide 122

(R)-6-(1,2-dihydroxyethyl)-4-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide 123

(S)-6-(1,2-dihydroxyethyl)-4-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide 124

(S)-4-(1,2-dihydroxyethyl)-6-(1- isobutyl-1H-indol-5-yl)picolinamide 125

(R)-4-(1,2-dihydroxyethyl)-6-(1- isobutyl-1H-indol-5-yl)picolinamide 126

(S)-6-(1,2-dihydroxyethyl)-4-(1- isobutyl-1H-indol-5-yl)picolinamide 129

6-(1-methyl-3-(3-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide130

6-(1-methyl-3-(4-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide131

6-(1-(2-(diethylamino)ethyl)-3-(4- fluorophenyl)-1H-indol-6-yl)picolinamide 138

6-amino-2-(benzofuran-5-yl)-N-(4- (trifluoromethyl)phenyl)pyrimidine-4-carboxamide 139

5-(6-((4- (trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid 140

5-(6-((4- (trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamide 141

(S)-2-(5-(6-((4- (trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3- carboxamido)pentanediamide 142

5-(6-carbamoylpyridin-2-yl)-1-(4- (trifluoromethyl)benzyl)-1H-indole-3-carboxamide 143

(S)-N-(1-amino-1-oxopropan-2-yl)-5- (6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3- carboxamide 144

(S)-6-(3-(((2-oxopyrrolidin-3- yl)amino)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-indol-5- yl)picolinamide 145

(S)-6-(1-(cyclohexylmethyl)-3-(((2- oxopyrrolidin-3-yl)amino)methyl)-1H-indol-5-yl)picolinamide 150

(2R,3S)-2,3-dihydroxy-3-(6-(1- isobutyl-1H-indol-5-yl)pyridin-2-yl)propanamide 151

(2R,3S)-2,3-dihydroxy-3-(6-(1-(4- (trifluoromethyl)benzyl)-1H-indol-5-yl)pyridin-2-yl)propanamide 152

(2R,3S)-3-(6-(1-(cyclohexylmethyl)- 1H-indol-5-yl)pyridin-2-yl)-2,3-dihydroxypropanamide 153

(2R,3S)-2,3-dihydroxy-3-(6-(1- isobutyl-1H-indol-5-yl)pyridin-2-yl)propanamide 154

(2R,3S)-3-(6-(1-(cyclopropylmethyl)- 1H-indol-5-yl)pyridin-2-yl)-2,3-dihydroxypropanamide 155

(2R,3S)-2,3-dihydroxy-3-(6-(1- isobutyl-1H-indazol-5-yl)pyridin-2-yl)propanamide 156

2-(1-(4-(trifluoromethyl)benzyl)-1H- indol-5-yl)thiazole-4-carboxamide

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a straight- orbranched-chain aliphatic hydrocarbon containing one to twelve carbonatoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atoms designated(i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkylsuch as propyl or isopropyl, etc.). In one embodiment, the alkyl groupis chosen from a straight chain C₁₋₁₀ alkyl group. In anotherembodiment, the alkyl group is chosen from a branched chain C₃₋₁₀ alkylgroup. In another embodiment, the alkyl group is chosen from a straightchain C₁₋₆ alkyl group. In another embodiment, the alkyl group is chosenfrom a branched chain C₃₋₆ alkyl group. In another embodiment, the alkylgroup is chosen from a straight chain C₁₋₄ alkyl group. In anotherembodiment, the alkyl group is chosen from a branched chain C₃₄ alkylgroup. In another embodiment, the alkyl group is chosen from a straightor branched chain C₃₄ alkyl group. Non-limiting exemplary C₁₋₁₀ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, andthe like. Non-limiting exemplary C₁ alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently chosen from nitro,haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, cycloalkyl, and the like. In one embodiment, theoptionally substituted alkyl is substituted with two substituents. Inanother embodiment, the optionally substituted alkyl is substituted withone substituent. Non-limiting exemplary optionally substituted alkylgroups include —CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh,—CH₂C₆H₁₁, and the like.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing one or two double bonds) cyclic aliphatichydrocarbons containing one to three rings having from three to twelvecarbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl group has two rings. Inone embodiment, the cycloalkyl group has one ring. In anotherembodiment, the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group.In another embodiment, the cycloalkyl group is chosen from a C₃₋₆cycloalkyl group. Non-limiting exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl,cyclohexenyl and the like.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted cycloalkyl is substituted with two substituents.In another embodiment, the optionally substituted cycloalkyl issubstituted with one substituent. Non-limiting exemplary optionallysubstituted cycloalkyl groups include:

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one, two or three carbon-to-carbon double bonds. In oneembodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. Inanother embodiment, the alkenyl group is chosen from a C₂ alkenyl group.Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one to three carbon-to-carbon triple bonds. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In oneembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,butynyl, 2-butynyl, pentynyl, and hexynyl groups.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “hydroxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more, e.g., one, two, or three, hydroxy groups.In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group,i.e., substituted with one hydroxy group. In another embodiment, thehydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with twohydroxy groups, e.g.,

In another embodiment, the hydroxyalkyl group is chosen from a C₁₋₄hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups includehydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, suchas 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted alkenylor optionally substituted alkynyl attached to a terminal oxygen atom. Inone embodiment, the alkoxy group is chosen from a C₁₋₄ alkoxy group. Inanother embodiment, the alkoxy group is chosen from a C₁₋₄ alkylattached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkylthio” as usedby itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group. In one embodiment,the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limitingexemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆-C₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with one to five substituents independently chosen fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, (cycloalkylamino)alkyl, (halo(C₁-C₄)alkoxy)alkyl, or(heteroaryl)alkyl. In one embodiment, the optionally substituted aryl isan optionally substituted phenyl. In one embodiment, the optionallysubstituted phenyl has four substituents. In another embodiment, theoptionally substituted phenyl has three substituents. In anotherembodiment, the optionally substituted phenyl has two substituents. Inanother embodiment, the optionally substituted phenyl has onesubstituent. Non-limiting exemplary substituted aryl groups include2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl,2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl,3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The termoptionally substituted aryl is meant to include groups having fusedoptionally substituted cycloalkyl and fused optionally substitutedheterocyclo rings. Examples include

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. A non-limiting exemplaryaryloxy group is PhO—.

For the purpose of the present disclosure, the term “heteroaryloxy” asused by itself or as part of another group refers to an optionallysubstituted heteroaryl attached to a terminal oxygen atom. Non-limitingexemplary heteroaryloxy groups include:

For the purpose of the present disclosure, the term “aralkyloxy” as usedby itself or as part of another group refers to an aralkyl groupattached to a terminal oxygen atom. A non-limiting exemplary aralkyloxygroup is PhCH₂O—.

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5 to 14 ring atoms (i.e., C₅-C₁₄ heteroaryl), wherein at leastone carbon atom of one of the rings is replaced with a heteroatomindependently selected from the group consisting of oxygen, nitrogen andsulfur. In one embodiment, the heteroaryl contains 1, 2, 3, or 4heteroatoms independently selected from the group consisting of oxygen,nitrogen and sulfur. In one embodiment, the heteroaryl has threeheteroatoms. In another embodiment, the heteroaryl has two heteroatoms.In another embodiment, the heteroaryl has one heteroatom. Non-limitingexemplary heteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl(e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl),pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl”is also meant to include possible N-oxides. Exemplary N-oxides includepyridyl N-oxide and the like.

In one embodiment, the heteroaryl is a 5- or 6-membered heteroaryl. Inone embodiment, the heteroaryl is a 5-membered heteroaryl, i.e., theheteroaryl is a monocyclic aromatic ring system having 5 ring atomswherein at least one carbon atom of the ring is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur.Non-limiting exemplary 5-membered heteroaryl groups include thienyl,furyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In anotherembodiment, the heteroaryl is a 6-membered heteroaryl, e.g., theheteroaryl is a monocyclic aromatic ring system having 6 ring atomswherein at least one carbon atom of the ring is replaced with a nitrogenatom. Non-limiting exemplary 6-membered heteroaryl groups includepyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with one to four substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedheteroaryl has one substituent. In one embodiment, the optionallysubstituted is an optionally substituted pyridyl, i.e., 2-, 3-, or4-pyridyl. Any available carbon or nitrogen atom can be substituted. Inanother embodiment, the optionally substituted heteroaryl is anoptionally substituted indole.

For the purpose of the present disclosure, the term “heterocycle” or“heterocyclo” as used by itself or as part of another group refers tosaturated and partially unsaturated (e.g., containing one or two doublebonds) cyclic groups containing one, two, or three rings having fromthree to fourteen ring members (i.e., a 3- to 14-membered heterocyclo)wherein at least one carbon atom of one of the rings is replaced with aheteroatom. Each heteroatom is independently selected from the groupconsisting of oxygen, sulfur, including sulfoxide and sulfone, and/ornitrogen atoms, which can be oxidized or quaternized. The term“heterocyclo” is meant to include groups wherein a ring —CH₂— isreplaced with a —C(═O)—, for example, cyclic ureido groups such as2-imidazolidinone and cyclic amide groups such as β-lactam, γ-lactam,δ-lactam, ε-lactam, and piperazin-2-one. The term “heterocyclo” is alsomeant to include groups having fused optionally substituted aryl groups,e.g., indolinyl. In one embodiment, the heterocyclo group is chosen froma 5- or 6-membered cyclic group containing one ring and one or twooxygen and/or nitrogen atoms. The heterocyclo can be optionally linkedto the rest of the molecule through a carbon or nitrogen atom.Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl,piperazin-2-one, piperazine-2,6-dione, 2-imidazolidinone, piperidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, (heteroaryl)alkyl, and the like. Substitution mayoccur on any available carbon or nitrogen atom, and may form aspirocycle. Non-limiting exemplary optionally substituted heterocyclogroups include:

In one embodiment, the optionally substituted heterocyclo is a 5- or6-membered optionally substituted heterocyclo. Non-limiting exemplary 5-or 6-membered optionally substituted heterocyclo groups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR¹⁵, wherein R¹⁵ isalkyl.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(16a)R^(16b),wherein R^(16a) and R^(16b) are each independently alkyl or R^(16a) andR^(16b) are taken together to form a 3- to 8-membered optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR¹⁷, whereinR¹⁷ is hydroxyalkyl.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to —NR^(19a)R^(19b),wherein R^(19a) is optionally substituted cycloalkyl and R^(19b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂ and the like.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with an alkylamino group. A non-limiting exemplary(alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group. Anon-limiting exemplary (dialkylamino)alkyl group is —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term“(cycloalkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a cycloalkylamino group.Non-limiting exemplary (cycloalkylamino)alkyl groups includeCH₂N(H)cyclopropyl, —CH₂N(H)cyclobutyl, and —CH₂N(H)cyclohexyl.

For the purpose of the present disclosure, the term“(halo(C₁-C₄)alkoxy)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a C₁-C₄ haloalkoxy group.Non-limiting exemplary (halo(C₁-C₄)alkoxy)alkyl groups include—CH₂OCH₂CF₃ and —CH₂OCF₃.

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. Non-limitingexemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “heterocycloamino”as used by itself or as part of another group refers to NR^(21a)R^(21b)wherein R^(21a) is optionally substituted heterocyclo and R^(21b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term“(heterocycloamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with one heterocycloamino group. Inone embodiment, the (heterocycloamino)alkyl is a C₁₋₄ alkyl substitutedwith one heterocycloamino group. Non-limiting exemplary(heterocycloamino)alkyl groups include:

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(24a)R^(24b), wherein R^(24a) and R^(24b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R^(24a) andR^(24b) taken together with the nitrogen to which they are attached forma 3- to 8-membered optionally substituted heterocyclo group. In oneembodiment, R^(24a) and R^(24b) are each independently hydrogen oroptionally substituted alkyl. Non-limiting exemplary carboxamido groupsinclude —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and —CON(H)Ph.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(23a)R^(23b), wherein R^(23a) and R^(23b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(23a) and R^(23b) taken together with thenitrogen to which they are attached from a 3- to 8-membered heterocyclogroup. Non-limiting exemplary sulfonamido groups include —SO₂NH₂,—SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. A non-limitingexemplary carboxyalkyl group is —CH₂CO₂H.

For the purpose of the present disclosure, the terms “aralkyl” or“arylalkyl” or “optionally substituted aralkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted aryl groups. In one embodiment, theoptionally substituted aralkyl group is a C₁₋₄ alkyl substituted withone optionally substituted aryl group. In one embodiment, the optionallysubstituted aralkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted aryl group. In one embodiment, the optionallysubstituted aralkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted phenyl group. Non-limiting exemplary optionallysubstituted aralkyl groups include benzyl, phenethyl, —CHPh₂,—CH₂(4-F-Ph), —CH₂(4-Me-Ph), —CH₂(4-CF₃-Ph), and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the terms “(cycloalkyl)alkyl”or “optionally substituted (cycloalkyl)alkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted cycloalkyl groups. In oneembodiment, the (cycloalkyl)alkyl group is a C₁₋₄ alkyl substituted withone optionally substituted cycloalkyl group. In one embodiment, the(cycloalkyl)alkyl group is a C₁ or C₂ alkyl substituted with oneoptionally substituted cycloalkyl group. In one embodiment, the(cycloalkyl)alkyl group is a C₁ or C₂ alkyl substituted with onecycloalkyl group. Non-limiting exemplary (cycloalkyl)alkyl groupsinclude:

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(22a)—C(═O)—NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(═O)—NH₂ and —NH—C(═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(25a)—C(═NR²⁶)—NR^(25b)R^(25c) wherein R^(25a), R^(25b), and R^(25c)are each independently hydrogen, alkyl, or optionally substituted aryl,and R²⁶ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl,carboxamido, or sulfonamido. Non-limiting exemplary guanidino groupsinclude —NH—C(═NH)—NH₂, —NH—C(═NCN)—NH₂, —NH—C(═NH)—NHCH₃ and the like.

For the purpose of the present disclosure, the terms “(heteroaryl)alkyl”or “optionally substituted (heteroaryl)alkyl” as used by themselves oras part of another group refers to an alkyl group substituted with one,two, or three optionally substituted heteroaryl groups. In oneembodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkyl substituted withone optionally substituted heteroaryl group. In one embodiment, the(heteroaryl)alkyl is a C₁ or C₂ alkyl substituted with one optionallysubstituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkylgroups include:

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable straight orbranched chain hydrocarbon radical containing 1 to 10 carbon atoms andat least two heteroatoms, which can be the same or different, selectedfrom O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) canoptionally be oxidized; and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position orterminal position of the heteroalkyl group, or at a position at whichthe heteroalkyl group is attached to the remainder of the molecule. Inone embodiment, the heteroalkyl group contains two oxygen atoms. Inanother embodiment, the heteroalkyl group contains two nitrogen atoms.In other embodiment, the heteroalkyl group contains one nitrogen atomand one oxygen atom. Non-limiting exemplary heteroalkyl groups include:

—CH₂N(H)CH₂CH₂N(CH₃)₂; —CH₂N(CH₃)CH₂CH₂N(CH₃)₂;—CH₂N(H)CH₂CH₂CH₂N(CH₃)₂; —CH₂N(H)CH₂CH₂OH; —CH₂N(CH₃)CH₂CH₂OH;—CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃; —CH₂NHCH₂CH₂OCH₂; —OCH₂CH₂NH₂; and—NHCH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the terms“(heterocyclo)alkyl” or “optionally substituted (heterocyclo)alkyl” asused by themselves or as part of another group refers to an alkyl groupsubstituted with one optionally substituted heterocyclo group, andoptionally one hydroxy group. In one embodiment, the (heterocyclo)alkylis a C₁₋₄ alkyl substituted with one optionally substituted heterocyclogroup and one hydroxy group. In one embodiment, the (heterocyclo)alkylis a C₁₋₄ alkyl substituted with one optionally substituted heterocyclogroup. In one embodiment, the (heterocyclo)alkyl is a C₁ or a C₂ alkylsubstituted with one optionally substituted heterocyclo group.Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one or two carboxamido groups, and optionally oneheterocyclo, amino, alkylamino, or dialkylamino group. In oneembodiment, the (carboxamido)alkyl is a C₁₋₄ alkyl substituted with onecarboxamido group. In another embodiment, the (carboxamido)alkyl is aC₁₋₄ alkyl substituted with two carboxamido groups. Non-limitingexemplary (carboxamido)alkyl groups include —CH₂CONH₂, —C(H)CH₃—CONH₂,—CH₂CON(H)CH₃, and —CH(CO₂NH₂)CH₂CH₂CO₂NH₂.

The present disclosure encompasses any of the Compounds of the Inventionbeing isotopically-labelled (i.e., radiolabeled) by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and¹⁴C. Isotopically-labeled Compounds of the Invention can be prepared bymethods known in the art.

The present disclosure encompasses ³H, ¹¹C, or ¹⁴C radiolabeledCompounds of the Invention and the use of any such compounds asradioligands for their ability to bind to the sodium channel. Forexample, one use of the labeled compounds of the present Invention isthe characterization of specific receptor binding. Another use of alabeled Compound of the Invention is an alternative to animal testingfor the evaluation of structure-activity relationships. For example, thereceptor assay can be performed at a fixed concentration of a labeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. For example, a tritiated Compound ofthe Invention can be prepared by introducing tritium into the particularcompound, for example, by catalytic dehalogenation with tritium. Thismethod may include reacting a suitably halogen-substituted precursor ofthe compound with tritium gas in the presence of a suitable catalyst,for example, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer,Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

Compounds of the Invention may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. The present invention is meant to encompass theuse of all such possible forms, as well as their racemic and resolvedforms and mixtures thereof. The individual enantiomers can be separatedaccording to methods known in the art in view of the present disclosure.When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that they include both E and Z geometric isomers. Alltautomers are intended to be encompassed by the present invention aswell.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present disclosure for thepurposes of amelioration or cure, including preemptive and palliativetreatment. In one embodiment, the term “treat,” “treating” or“treatment” is meant to encompass administering to a subject a Compoundof the Invention for the purposes of amelioration or cure.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The Invention encompasses the preparation and use of salts of theCompounds of the Invention, including non-toxic pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Invention with a solution of a pharmaceuticallyacceptable non-toxic acid, such as, hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the Compound ofthe Invention with a solution of a pharmaceutically acceptable non-toxicbase (such as, sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate and the like).

The Invention also encompasses the preparation and use of solvates ofCompounds of the Invention. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present invention with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present invention is about 2:1, about 1:1 orabout 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Invention can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that theInvention includes both solvated and unsolvated forms of the compoundsdescribed supra. One type of solvate is a hydrate. A “hydrate” relatesto a particular subgroup of solvates where the solvent molecule iswater. Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Invention in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

In certain embodiments, Compounds of the Invention can act as blockersof one or more sodium (Na⁺) channels. Consequently, a number of diseasesand conditions mediated by sodium ion influx can be treated by employingthese compounds. The Invention also provides a method for treating adisorder responsive to blockade of sodium channels in an animalsuffering from, or at risk of suffering from, said disorder, said methodcomprising administering to the animal an effective amount of one ormore Compounds of the Invention.

The invention is further directed to a method of modulating sodiumchannels in an animal in need thereof, said method comprisingadministering to the animal a modulating-effective amount of at leastone Compound of the Invention.

In certain embodiments, the Invention provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, neuronalloss following global and focal ischemia, pain (e.g., acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, theInvention provides a method of treating pain. In another embodiment, thetype of pain is chronic pain. In another embodiment, the type of pain isneuropathic pain. In another embodiment, the type of pain ispostoperative pain. In another embodiment, the type of pain isinflammatory pain. In still another embodiment, the type of pain issurgical pain. In another embodiment, the type of pain is acute pain.

In a separate embodiment, the treatment of pain (e.g., chronic pain,such as neuropathic pain, postoperative pain, or inflammatory pain,acute pain or surgical pain) is preemptive. In another embodiment, thetreatment of pain is palliative. In each instance, such method oftreatment requires administering to an animal in need of such treatmentan amount of a Compound of the Invention that is therapeuticallyeffective in achieving said treatment. In one embodiment, the amount ofsuch compound is the amount that is effective to block sodium channelsin vitro. In one embodiment, the amount of such compound is the amountthat is effective to block sodium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 18:387-391 (2000)).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogeneous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as the pain from whichdiabetics suffer.

The Invention is also directed to the use of a Compound of the Inventionin the manufacture of a medicament for treating a disorder responsive tothe blockade of sodium channels (e.g., any of the disorders listedabove) in an animal suffering from said disorder.

General Synthesis of Compounds

Compounds of Formula I can be made using conventional organic synthesisin view of the present disclosure, or by the illustrative methods shownin the Schemes below:

Compound A is converted to Compound C by reaction with Compound B, whereBR′R″ is a boronic acid or ester, in the presence of a suitable catalyst(such as, Pd(dppf)Cl₂) and a suitable base (such as, KOAc) in a suitablesolvent (such as, DMF).

Compound D, where Q¹ and Q² are a suitable leaving group (such as,halide, triflate, tosylate, mesylate, etc.) is converted to Compound Fby reaction with Compound E in the presence of a suitable base (such as,DIPEA) in a suitable solvent (such as, CAN). Note that the activehydrogen in Compound E is attached to an appropriate heteroatom (suchas, N, O, S, etc.). Compound F is converted to Compound G by reactionwith Compound C in the presence of a suitable catalyst (such as,Pd(PPh₃)₂Cl₂) and a suitable base (such as, Na₂CO₃) in a suitablesolvent (such as, DME).

Compound H, where V is either a boronic acid/ester or a suitableheterocycle (such as, that in Compound F) is converted to Compound I byreaction with the appropriate acid chloride, carbamoyl chloride, etc. inthe presence of a suitable base (such as, DIPEA) in a suitable solvent(such as, DCM). Compound H is converted to Compound J by eitheralkylation with a suitable alkyl halide, triflate, tosylate, mesylate,etc. in the presence of a suitable base (such as, DIPEA or NaH) in asuitable solvent (such as, ACN or DMF) or by reductive ammination withthe appropriate aldehyde in the presence of a suitable reducing agent(such as, NaBH(OAc)₃) in a suitable solvent (such as, DCM). Compound His converted to Compound K by reaction with the appropriate sulfonylchloride in the presence of a suitable base (such as, DIPEA) in asuitable solvent (such as, DCM).

Compound L, where A¹ is either Q² or a suitable heterocycle (such as,that in Compound C) is converted to Compound N by reaction with CompoundM in the presence of a suitable catalyst (such as, Pd(dppf)Cl₂) and asuitable base (such as, Na₂CO₃) in a suitable solvent (such as, aq.Dioxane). Compound N can be converted to Compound O by reaction with asuitable reagent (such as, OsO₄) in a suitable solvent (such as, aq.Acetone), or with a suitable chiral reagent (such as, AD-mix alpha orbeta) in a suitable solvent (such as, aq. t-BuOH).

Subsequent side chain modifications can be accomplished via appropriatefunctional group manipulations well known to one of ordinary skills inthe art.

Testing of Compounds

In certain embodiments, Compounds of the Invention are effective intreating pain, e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain, postoperative pain, and inflammatory pain,or surgical pain

Further, certain Compounds of the Invention were assessed by sodiummobilization and/or electrophysiological assays for sodium channelblocker activity. One aspect of the invention is based on the use of theCompounds of the Invention as sodium channel blockers. Based upon thisproperty, Compounds of the Invention are considered useful in treating acondition or disorder responsive to blockade of one or more sodium ionchannels, e.g., stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, cardiacarrhythmia, or providing local anesthesia.

In a separate embodiment, the present invention is directed to compoundsthat are blockers of sodium channels. According to the presentinvention, those compounds having useful sodium channel blockingproperties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less,about 10 μM or less, about 5 μM or less, or about 1 μM or less, insodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Invention exhibit an IC₅₀ for Na_(v)1.7 of100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μM orless, about 5 μM or less, about 1 μM or less, about 0.5 μM or less,about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less.Compounds of the Invention can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, Compounds of the Invention demonstrate substantiallyno penetration across the CNS blood-brain barrier in a mammal Suchcompounds are referred to as “peripherally restricted” as a means todesignate their PNS versus CNS tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Invention is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theInvention can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols

FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J. Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer, to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism Program, version 4.0 or higher(available from GraphPad Software, San Diego, Calif.) to determine theIC₅₀ value for the test article. At least one standard referencecompound was evaluated during each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(V)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate was then incubated in growth media, with orwithout selective antibiotic, overnight at 37° C. at 5% CO₂, 95%humidity, in preparation for the assay. For counter-screens of othervoltage-gated sodium channels, the procedure was very similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3) and then pre-incubated with the test articles, CoroNa™Green AM sodium dye (for cell loading) and KCl for re-polarization andsynchronization of the channels in the entire population of cells. Forthis dye-loading and pre-stimulation step, the components were added asfollows, immediately after the wash step: 1) first, the compounddilutions and controls were added as 4× concentrates in assay buffer at50 μL/well; 2) CoroNa™ Green AM dye was diluted from the stock solutionto 20 μM in assay buffer (4× concentrate) and added to the plate at 50μL/well; and 3) finally, a solution of 180 mM KCl (2×) was prepared bydiluting a 2M stock solution into assay buffer and the solution wasadded to the cells at 100 μl/well. The cells were incubated at 25° C. inthe dark for 30 mM before their fluorescence was measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA®) or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions are filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gated sodium channels or otherbiologically relevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(V)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for 120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells Manual Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells are used approximately 12-48 hours after plating.

Cells Automated Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on tissue cultureflasks in standard DMEM culture media (Mediatech, Inc.) and incubated ina 5% CO₂ incubator at 37° C. Cultured cells are used approximately 12-48hours after plating.

Manual Electrophysiology:

On the day of experimentation, the 35 mm dish is placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system is used to apply test solutionsdirectly to the cell under evaluation. This “shooter” system consists ofan array of glass pipettes connected to a motorized horizontaltranslator. The outlet of the shooter is positioned approximately 100 μmfrom the cell of interest.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealsare formed and the whole-cell configuration is established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 channels arerecorded. Borosilicate glass pipettes with resistance values between 1.5and 2.0 MΩ when filled with pipette solution are used and seriesresistance (<5 MΩ) is compensated by 75-80%. Signals are sampled at 50kHz and low pass filtered at 3 kHz.

Automated Electrophysiology:

On the day of experimentation, cells are prepared by removing media anddigesting with appropriate enzymes to suspend cells in externalsolution.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Patchliner (Nanion Technologies, Munich Germany),EPC 10 quadro amplifiers (HEKA, Bellmore, N.Y.) and PatchControl HT10905 (Nanion Technologies) and PatchMaster v2x73 software (HEKA) andstored on a personal computer. Gigaseals are formed and the whole-cellconfiguration is established in voltage clamp mode, and membranecurrents generated by hNa_(v)1.7 are recorded. NPC-16 chips haveresistance values between 1.0 and 2.0 MΩ when filled with pipettesolution and series resistance (<5 MΩ). Signals are sampled at 25 kHzand low pass filtered at 3 kHz.

Voltage protocols Manual Electrophysiology:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols are run to establish the 1) test potential (V_(max)),2) holding potential (V_(h)), and 3) the conditioning potential for eachcell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol is run to determine the potential at which themaximal current (I_(max)) is elicited. This potential is the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels are in the inactivated state, a standard steady-stateinactivation (SSIN) protocol is run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse to V_(max). This protocol also permitsdetermination of the holding potential at which all channels are in theresting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) is generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell isdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolis repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline is established, the test compound is applied andblock of the current elicited by the test pulse assessed. In some cases,multiple cumulative concentrations are applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound is attempted by superfusing with control solution oncesteady-state block is observed. An estimate of the K_(t) is calculatedas follows:K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) is determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents is as follows. After establishing the whole-cell configurationin voltage clamp mode, two voltage protocols were run to establish: 1)the holding potential; and 2) the test potential for each cell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol is run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (V_(h1)) is typically 20 mVmore hyperpolarized than the first potential where inactivation isobserved with the inactivation protocol.

From this holding potential a standard I-V protocol is run to determinethe potential at which the maximal current is elicited (V_(max)). Thispotential is the test potential (V_(t)).

The compound testing protocol is a series of 10 ms depolarizations fromthe Vh1 (determined from the SSIN) to the V_(t) (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline isestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides 50% block) isapplied and block of the current assessed. Washout of the compound isattempted by superfusing with control solution once steady-state blockwas observed. The affinity for the resting state of the channels iscalculated as follows:K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential isdepolarized such that 20-50% of the current amplitude is reduced whenpulsed to the same V_(t) as above. This is the second holding potential(V_(h2)). The magnitude of this depolarization depends upon the initialcurrent amplitude and the rate of current loss due to slow inactivation.The current reduction is recorded to determine the fraction of availablechannels at this potential (h).h=I@V _(h2) /I _(max).  Eq. 4

At this membrane voltage a proportion of channels are in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents are elicited by 10 ms voltage steps from V_(h2) toV_(t) every 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound is applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses are measuredwith respect to a projected baseline to determine K_(app).K _(app)=[drug]*{FR/(1−FR)},  Eq. 5where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, areused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:Ki=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Voltage protocols Automated Electrophysiology:

Similar voltage protocols are used as described above, however the testpotential (V_(t)) is set to a predetermined voltage. K_(app) isdetermined as described above.

Solutions and Chemicals:

For electrophysiological recordings the external solution is eitherstandard, HBSS supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contains (in mM):NaCl (10), CsF (140), CaCl2 (1), MgCl2 (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds are prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO doesnot affect sodium currents. Vehicle solution used to establish base linealso contains 0.3% DMSO.

Data analysis Manual Electrophysiology:

Data is analyzed off-line using Clampfit software (pClamp, v.8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

Data analysis Automated Electrophysiology:

Data is analyzed off-line using Igor Pro (v 6.2.2.2; Wave Metrics, Inc.,Lake Oswego, Oreg.) and Microsoft XL (Microsoft Office 2010, v14x,Microsoft, Renton Wash.).

In Vivo Assay for Pain

Compounds of the Disclosure can be tested for their antinociceptiveactivity in the formalin model as described in Hunskaar et al., J.Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30g; Harlan, San Diego, Calif.) can be used in all experiments. Food iswithdrawn on the day of the experiment. Mice are placed in Plexiglassjars for at least 1 hour to acclimate to the environment. Following theacclimation period, mice are weighed and given either the compound ofinterest administered i.p. or p.o., or the appropriate volume of vehicle(for example, 10% Tween-80 or 0.9% saline, and other pharmaceuticallyacceptable vehicles) as control. Fifteen minutes after the i.p. dosing,and 30 minutes after the p.o. dosing mice are injected with formalin (20μL of 5% formaldehyde solution in saline) into the dorsal surface of theright hind paw. Mice are transferred to the Plexiglass jars andmonitored for the amount of time spent licking or biting the injectedpaw. Periods of licking and biting are recorded in 5-minute intervalsfor 1 hour after the formalin injection. All experiments are done in ablinded manner during the light cycle. The early phase of the formalinresponse is measured as licking/biting between 0-5 minutes, and the latephase is measured from 15-50 minutes. Differences between vehicle anddrug treated groups can be analyzed by one-way analysis of variance(ANOVA). A P value <0.05 is considered significant. Compounds areconsidered to be efficacious for treating acute and chronic pain if theyhave activity in blocking both the early and second phase offormalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals: Each experiment uses rats weighing between 200-260 g atthe start of the experiment. The rats are group-housed and have freeaccess to food and water at all times, except prior to oraladministration of a test compound when food is removed for 16 h beforedosing. A control group acts as a comparison to rats treated with aCompound of the Disclosure. The control group is administered thecarrier as used for the test compound. The volume of carrieradministered to the control group is the same as the volume of carrierand test compound administered to the test group.

Inflammatory Pain:

To assess the actions of Compounds of the Disclosure on the treatment ofinflammatory pain, the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).Prior to the injury, the animal is assessed for response to noxiousmechanical stimuli by determining the paw withdrawal threshold (PWT), orto noxious thermal stimuli by determining paw withdrawal latency (PWL),as described below (baseline PWT or PWL). Then, the left hind paw ofeach animal is administered a 50 μL intraplantar injection of 50% FCA.24 hour post injection, the PWT or PWL is again assessed(pre-administration PWT or PWL). Rats are then administered a singleinjection of either a test compound or 30 mg/Kg of a positive controlcompound (e.g., indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (post-administration PWT or PWL). Percentage reversal ofhyperalgesia for each animal is defined as:

${\%\mspace{14mu}{reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu}{administration}\mspace{14mu} P\; W\; T\mspace{14mu}{or}\mspace{14mu} P\; W\; L} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T\mspace{14mu}{or}\mspace{14mu} P\; W\; L} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} P\; W\; T\mspace{14mu}{or}\mspace{14mu} P\; W\; L} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T\mspace{14mu}{or}\mspace{14mu} P\; W\; L} \right)\end{bmatrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins. The animals are assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours afteradministration of either drug or vehicle, for the ipsilateral (injuredside) rear paw of the animal. Percentage reversal of neuropathichyperalgesia is defined as:

${\%\mspace{14mu}{reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu}{administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation (SNL) model of neuropathicpain is used to produce mechanical hyperalgesia, thermal hyperalgesia,and tactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theDisclosure or vehicle, for the left rear paw of the animal. The animalscan also be assessed for response to noxious thermal stimuli or fortactile allodynia, as described below. The Chung model for neuropathicpain is described in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Representative Compounds of the Disclosure can be tested in theSNL-induced mechanical hyperalgesia model in rats. Sensitivity tonoxious mechanical stimuli are measured in animals using the pawpressure test to assess mechanical hyperalgesia. In rats, hind pawwithdrawal thresholds (“PWT”), measured in grams, in response to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy), as described inStein (Biochemistry & Behavior 31: 451-455 (1988)). The rat's paw isplaced on a small platform, and a punctate weight was applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Disclosure can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice or rats, including the maximum electroshockseizure test (MES). Maximum electroshock seizures are induced in maleNSA mice weighing between 15-20 g and in male Sprague-Dawley ratsweighing between 200-225 g by application of current (for mice: 50 mA,60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using aUgo Basile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Compounds of the Invention can be administered to a mammal in the formof a raw chemical without any other components present. Compounds of theInvention can also be administered to a mammal as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a Compound of the Invention is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Invention is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose. While individual needs may vary, a determination of optimalranges of effective amounts of each compound is within the skill of theart. Typically, a Compound of the Invention can be administered to amammal, e.g., a human, orally at a dose of from about 0.0025 to about1500 mg per kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt or solvate thereof, per day to treatthe particular disorder. A useful oral dose of a Compound of theInvention administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt or solvate thereof. For intramuscularinjection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Invention, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt or solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa Compound of the Invention. Foremost among such animals are mammals,e.g., humans and companion animals, although the disclosure is notintended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the Compoundof the Invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the invention can beadministered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a Compound of the Invention. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

Compounds of the Invention (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein. In one embodiment, a Compound of theInvention is administered concurrently with a second therapeutic agent;for example, a single composition comprising both an effective amount ofa Compound of the Invention and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentinvention further provides a pharmaceutical composition comprising acombination of a Compound of the Invention, the second therapeuticagent, and a pharmaceutically acceptable carrier. Alternatively, a firstpharmaceutical composition comprising an effective amount of a Compoundof the Invention and a second pharmaceutical composition comprising aneffective amount of the second therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a Compoundof the Invention is administered prior or subsequent to administrationof an effective amount of the second therapeutic agent. In thisembodiment, the Compound of the Invention is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Inventionexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

A pharmaceutical composition of the present invention is manufactured ina manner which itself will be known in view of the instant disclosure,for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the Invention.

EXAMPLES Example 1 Synthesis of(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide(Compound 5)

A mixture of Compound 1 (34.8 g, 0.20 mol, Aldrich), phosphorusoxychloride (100 mL, 1.09 mol) and 20 drops of DMF were heated at 110°C. overnight. After cooling to RT the dark mixture was diluted withhexanes (500 mL) and vigorously stirred. The hexane layer was decanted,quickly washed with water (100 mL), brine (100 mL) and dried over MgSO₄.The organic layer was filtered and carefully evaporated in vacuo to giveCompound 2 as a light yellow liquid (26.13 g). Yield 62%. ¹H NMR (400MHz, CDCl₃): δ 7.93 (s, 1H).

To a solution of Compound 2 (26.13 g, 123.6 mmol) in Et₂O (500 mL) wasadded a mixture of 0.5M NH₃ in dioxane (250 mL, 125 mmol) and DIPEA (22mL, 126 mmol) dropwise over 50 min. After stirring at RT overnight thereaction mixture was concentrated in vacuo to give a residue that waspurified by flash chromatography (SiO₂, 10-50% EtOAc/hexanes). Theproduct obtained was triturated with 10 mL 10% EtOAc/hexanes andfiltered to give Compound 3 as an orange crystalline solid (9.743 g).Yield 41%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (br s, 1H), 8.16 (br s,1H), 8.10 (s, 1H). LC/MS: m/z=192 [M+H]⁺ (Calc: 191).

To a solution of Compound 3 (4.80 g, 25.0 mmol) in ACN (100 mL) wasadded (S)-2-aminopropane carboxamide hydrochloride (Compound 4) (3.18 g,25.54 mmol) and DIPEA (9.60 mL, 55.11 mmol). The mixture was heated at50° C. overnight then concentrated. The residue was purified by flashchromatography (SiO₂, 20-60% acetone/hexanes) to give Compound 5 as apale tan powder (4.81 g). Yield 79%. LC/MS: m/z=244 [M+H]⁺ (Calc: 243).

In a similar manner the following compounds were prepared:

(S)-2-chloro-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide(Compound 6): LC/MS: m/z=256 [M+H]⁺ (Calc: 255); and

(S)-2-chloro-6-((2-oxopyrrolidin-3-yl)oxy)pyrimidine-4-carboxamide(Compound 7): LC/MS: m/z=257 [M+H]⁺ (Calc: 256).

Example 2 Synthesis of methyl(S)-2-chloro-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxylate(Compound 10)

Compound 8 (2.07 g, 10.0 mmol) and Compound 9 (1.00 g, 10.0 mmol) weredissolved in ACN (10 mL) and cooled to 0° C. DIPEA (1.67 mL, 10.0 mmol)was added dropwise. After the addition was complete the mixture wasallowed to stir at RT overnight. The mixture was diluted with 1:4ACN/water (25 mL) and the solid that formed was filtered to giveCompound 10 as a white solid (2.00 g). Yield 74%. LC/MS: m/z=271 [M+H]⁺(Calc: 270).

In a similar manner methyl(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxylate(Compound 11) was prepared:

LC/MS: m/z=259 [M+H]⁺ (Calc: 258).

Example 3 Synthesis of(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxylicacid (Compound 12)

Compound 11 (1.20 g, 4.64 mmol) was dissolved in 2:1 MeOH/water (15 mL)and KOH (0.53 g, 9.28 mmol) was added. The resulting mixture was stirredat RT for 2 h and concentrated. The residue was dissolved in water (20mL), cooled to 0° C. and the pH adjusted to 4 using conc. HCl. Theresulting solid was filtered to give Compound 12 as an off-white solid(1.00 g). Yield 88%. LC/MS: m/z=245 [M+H]⁺ (Calc: 244).

Example 4 Synthesis of2-(2,4-dimethoxyphenyl)-1-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(Compound 20)

A mixture of Compound 13 (6.70 g, 60.3 mmol), Compound 14 (11.3 g, 60.3mmol) and Cs₂CO₃ (39.3 g, 121 mmol) in NMP (150 mL) was heated at 150°C. for 1.5 h. The mixture was cooled to RT and diluted with water. Themixture was extracted with DCM and the organic extracts washed withwater, brine dried over MgSO₄ and concentrated. The residue was purifiedby flash chromatography (SiO₂, 0-100%, EtOAc/hexanes) to give Compound15 as a red solid (10.7 g). Yield 57%. LC/MS: m/z=312 [1\4+H]⁺ (Calc:311).

Fe (15.37 g, 275 mmol) and FeCl₃.H₂O (1.86 g, 6.88 mmol), were added toa solution of Compound 15 (10.7 g, 34.4 mmol) in 5:1 EtOH/AcOH (120 mL).The mixture was stirred at 60° C. for 3 h and cooled to RT. The mixturewas filtered through a pad of Celite and the pad washed with DCM and 1Naq. NaOH. The layers were separated and the aqueous layer extracted withDCM, dried over MgSO₄ and concentrated. The residue was purified byflash chromatography (SiO₂, 0-100%, EtOAc/hexanes) to give Compound 16as an off-white solid (6.90 g). Yield 71%. LC/MS: m/z=282 [M+H]⁺ (Calc:281).

To a solution of Compound 16 (1.136 g, 4.0 mmol) in EtOH (10 mL) wasadded Compound 17 (0.665 g, 4.0 mmol) and 40% aq. NaHSO₃ (5 mL) at RT.The reaction mixture was heated at 150° C. in a microwave reactor(Milestone MicroSYNTH) for 30 min After cooling to RT the reactionmixture was diluted water and extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, concentrated and the residuepurified by flash chromatography (SiO₂, 0-15% MeOH/DCM) to give Compound18 as an off-white solid (0.478 g). Yield 28%. LC/MS: m/z=428 [M+H]⁺(Calc: 427).

To a solution of Compound 18 (1.810 g, 4.24 mmol), Compound 19 (1.13 g,4.45 mmol), and potassium acetate (1.25 g, 12.71 mmol) in DMF (20 mL)was added Pd(dppf)Cl₂ DCM adduct (0.173 g, 0.21 mmol). The reaction washeated at 90° C. overnight then cooled to RT, quenched with water andextracted with EtOAc (2×). The combined organics were dried over MgSO₄and concentrated. The residue was purified by flash chromatography(SiO₂, 0-50% EtOAc/hexanes) to give Compound 20 as an off-white solid(0.924 g). Yield 46%. LC/MS: m/z=475 [M+H]⁺ (Calc: 474).

Example 5 Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole(Compound 25)

To a solution of Compound 21 (2.51 g, 12.7 mmol) in DMF (30 mL) at 0° C.was added sodium hydride (60% in mineral oil, 0.61 g, 15.30 mmol). Thereaction mixture was warmed to RT and stirred for 20 min then cooled to0° C. and Compound 22 (2.30 g, 14.03 mmol) was added in one portion. Thereaction mixture was stirred at RT for 4 h then carefully quenched withwater and extracted with EtOAc (2×). The combined organic layers werewashed with water (3×) and brine then dried over MgSO₄ and concentrated.The residue was purified by flash chromatography (SiO₂, 0-10%EtOAc/hexanes) to provide Compound 23 (1.43 g, 33%) and Compound 24(1.56 g, 36%) as off-white solids. Compound 23: LC/MS: m/z=342 [M+H]⁺(Calc: 341). Compound 24: LC/MS: m/z=342 [M+H]⁺ (Calc: 341).

To a solution of Compound 23 (1.43 g, 4.20 mmol), Compound 19 (1.13 g,4.45 mmol), and potassium acetate (1.25 g, 12.71 mmol) in 1,4-dioxane(20 mL) was added Pd(dppf)Cl₂ DCM adduct (0.173 g, 0.21 mmol). Thereaction was heated at 90° C. overnight then cooled to RT, quenched withwater and extracted with EtOAc (2×). The combined organics were driedover MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-40% EtOAc/hexanes) to give Compound 25 as anoff-white solid (1.06 g). Yield 65%. LC/MS: m/z=389 [M+H]⁺ (Calc: 388).

In a similar manner5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole(Compound 26) was prepared:

LC/MS: m/z=389 [M+H]⁺ (Calc: 388).

Example 6 Synthesis of 6-(1H-indol-5-yl)picolinamide (Compound 29),6-(1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide (Compound32) and 6-(1H-indol-5-yl)-N,N-bis(4-(trifluoromethyl)phenyl)picolinamide(Compound 33)

To a solution of Compound 27 (288 mg, 1.79 mmol, Combi-Blocks) andCompound 28 (300 mg, 1.49 mmol, Sigma-Aldrich) in DME (3 mL) and EtOH (3mL) was added Pd(PPh₃)₂Cl₂ (52 mg, 0.075 mmol) followed by 2M aq. Na₂CO₃(1.87 mL, 3.74 mmol). The reaction mixture was purged with nitrogen andstirred at 85° C. for 1.5 h. After cooling to RT, the reaction wasdiluted with water and extracted with EtOAc (2×). The combined organiclayers were dried over MgSO₄ and concentrated. The residue was purifiedby flash chromatography (SiO₂, 50-70% EtOAc/hexanes) to give Compound 29as a light brown solid (340 mg). Yield 96% An analytical sample wasobtained by precipitation from hot EtOAc/hexanes as a light beige solid.¹H NMR (400 MHz, DMSO-d₆) δ: 11.22 (br. s., 1H), 8.51 (s, 1H), 8.28 (br.s., 1H), 8.13-8.16 (m, 1H), 8.05 (dd, J=8.6, 1.5 Hz, 1H), 7.99 (t, J=7.8Hz, 1H), 7.86-7.92 (m, 1H), 7.69 (br. s., 1H), 7.48 (d, J=8.6 Hz, 1H),7.40 (t, J=2.6 Hz, 1H), 6.54 (t, J=2.0 Hz, 1H). LC/MS: m/z=238 [M+H]⁺(Calc: 237).

In a pressure vial equipped with stir bar was weighed(trans)-N1,N2-dimethylcyclohexane-1,2-diamine (Compound 31) (14 mg, 0.10mmol) and 1-iodo-4-(trifluoromethyl)benzene (Compound 30) (150 mg, 0.55mmol). Compound 29 (119 mg, 0.50 mmol), K₂CO₃ (146 mg, 1.05 mmol),copper(I) iodide (10 mg, 0.05 mmol) and DMF (1 mL) were added. The vialwas flushed with nitrogen, sealed and stirred at 110° C. in an oil bathfor 48 h. The reaction was cooled to RT, quenched with water andextracted with EtOAc (2×). The combined organic layers were washed withwater (2×) and brine then dried over MgSO₄ and concentrated. The residuewas purified by flash chromatography (SiO₂, 30-40% EtOAc/hexanes) toafford first Compound 33 as a pale yellow solid (60 mg; Yield 23%)followed by Compound 32 as an off-white solid (43 mg; Yield 22%).

Compound 33: ¹H NMR (400 MHz, DMSO-d₆) δ: 10.86 (s, 1H), 8.76 (d, J=1.5Hz, 1H), 8.26-8.35 (m, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.14 (t, J=7.7 Hz,1H), 8.08 (dd, J=7.7, 0.9 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.93 (d,J=8.6 Hz, 2H), 7.88 (d, J=3.3 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.79 (d,J=8.6 Hz, 2H), 6.93 (d, J=3.3 Hz, 1H). LC/MS: m/z=526 [M+H]⁺ (Calc:525).

Compound 32: ¹H NMR (400 MHz, DMSO-d₆) δ: 11.27 (br. s., 1H), 10.83 (s,1H), 8.59 (d, J=1.3 Hz, 1H), 8.25 (dd, J=7.9, 0.9 Hz, 1H), 8.19 (d,J=8.6 Hz, 2H), 8.14 (dd, J=8.6, 1.8 Hz, 1H), 8.09 (t, J=7.7 Hz, 1H),8.03 (dd, J=7.5, 0.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz,1H), 7.43 (t, J=2.6 Hz, 1H), 6.58 (t, J=2.0 Hz, 1H). LC/MS: m/z=382[M+H]⁺ (Calc: 381).

In a similar manner the following compounds were prepared:

6-(1-methyl-1H-indol-5-yl)picolinamide (Compound 34): LC/MS: m/z=252[M+H]⁺ (Calc: 251);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1H-indol-5-yl)pyrimidine-4-carboxamide(Compound 35): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.80 (s, 1H), 8.30 (d,J=7.20 Hz, 1H), 7.49 (d, J=7.20 Hz, 1H), 7.25 (s, 1H), 7.10 (s, 1H),6.60 (m, 1H), 4.70 (m, 1H), 1.60 (m, 3H). LC/MS: m/z=325 [M+H]⁺ (Calc:324);

(S)-2-(1H-indol-5-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide(Compound 36): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.70 (s, 1H), 8.30 (d,J=7.20 Hz, 1H), 7.41 (d, J=7.20 Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H),6.60 (m, 1H), 4.75 (m, 1H), 3.50 (m, 2H), 2.70 (m, 1H), 2.30 (m, 1H).LC/MS: m/z=337 [M+H]⁺ (Calc: 336);

(S)-2-(1H-indol-5-yl)-6-((2-oxopyrrolidin-3-yl)oxy)pyrimidine-4-carboxamide(Compound 37): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.80 (s, 1H), 8.35 (d,J=7.20 Hz, 1H), 7.48 (d, J=7.20 Hz, 1H), 7.29 (m, 2H), 6.60 (m, 1H),6.05 (m, 1H), 3.55 (m, 2H), 2.85 (m, 1H), 2.30 (m, 1H). LC/MS: m/z=338[M+H]⁺ (Calc: 337);

(S)-2-(1H-indol-5-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxylicacid (Compound 38): LC/MS: m/z=338 [M+H]⁺ (Calc: 337);

6-(1H-indol-5-yl)picolinic acid (Compound 39): LC/MS: m/z=239 [M+H]⁺(Calc: 238);

(S)-2-(1H-indol-5-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxylicacid (Compound 40): LC/MS: m/z=338 [M+H]⁺ (Calc: 337);

6-(1-isobutyl-1H-indol-5-yl)-N-(1,2,4-thiadiazol-5-yl)pyridine-2-sulfonamide(Compound 41): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.12-8.16 (m, 2H), 7.99 (d,J=7.9 Hz, 1H), 7.89 (t, J=7.8 Hz, 1H), 7.74 (dd, J=8.7, 1.7 Hz, 1H),7.70 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.11-7.15 (m, 1H), 6.41(d, J=3.1 Hz, 1H), 3.88 (d, J=7.5 Hz, 2H), 2.10 (dquin, J=13.6, 6.8 Hz,1H), 0.82 (d, J=6.6 Hz, 6H). LC/MS: m/z=414 [M+H]⁺ (Calc: 413);

(S)-2-(2-(2,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide(Compound 42): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.78 (s, 1H), 8.63 (d, J=9.2Hz, 1H), 7.46-7.53 (m, 3H), 7.39-7.45 (m, 2H), 7.29 (t, J=8.6 Hz, 2H),7.01 (s, 1H), 6.61 (dd, J=8.7, 2.1 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 3.79(s, 3H), 3.60 (s, 3H), 3.36-3.48 (m, 2H), 2.49-2.61 (m, 1H), 2.13-2.26(m, 1H). LC/MS: m/z=568 [M+H]⁺ (Calc: 567);

1-(4-(trifluoromethyl)phenyl)-5-(4-vinylpyrimidin-2-yl)-1H-benzo[d]imidazole(Compound 43): LC/MS: m/z=367 [M+H]⁺ (Calc: 366);

(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidine-4-carboxamide(Compound 44): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.86 (s, 1H), 8.69 (s, 1H),8.58 (d, J=8.8 Hz, 1H), 7.93 (q, J=8.8 Hz, 4H), 7.81 (d, J=8.6 Hz, 1H),7.06 (s, 1H), 4.68 (br. s., 1H), 3.28-3.34 (m, 2H), 2.46-2.58 (m, 1H),2.20 (br. s., 1H). LC/MS: m/z=482 [M+H]⁺ (Calc: 481);

(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)pyrimidine-4-carboxamide(Compound 45): ¹H NMR (400 MHz, MeOH-d₄) δ: 9.00 (s, 1H), 8.73 (s, 1H),8.51 (dd, J=8.8, 1.3 Hz, 1H), 7.83-7.96 (m, 4H), 7.64 (d, J=8.8 Hz, 1H),6.95 (s, 1H), 4.79-4.83 (m, 1H), 3.36-3.50 (m, 2H), 2.49-2.60 (m, 1H),2.13-2.28 (m, 1H). LC/MS: m/z=482 [M+H]⁺ (Calc: 481);

6-(3-Formyl-1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide(Compound 46): LC/MS: m/z=410 [M+H]⁺ (Calc: 409);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-isobutyl-1H-indol-5-yl)pyrimidine-4-carboxamide(Compound 47): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.70 (d, J=1.1 Hz, 1H), 8.26(dd, J=8.7, 1.4 Hz, 1H), 8.21 (br. s., 1H), 7.82 (br. s., 1H), 7.67 (br.s., 1H), 7.49 (br. s., 1H), 7.43 (d, J=8.8 Hz, 1H), 7.33 (d, J=3.1 Hz,1H), 6.97 (d, J=7.5 Hz, 2H), 6.45 (d, J=3.1 Hz, 1H), 4.58 (br. s., 1H),3.95 (d, J=7.3 Hz, 2H), 2.07 (dquin, J=13.6, 6.8 Hz, 1H), 1.33 (d, J=7.0Hz, 3H), 0.80 (d, J=6.6 Hz, 6H). LC/MS: m/z=381 [M+H]⁺ (Calc: 380); and6-(1-Isobutyl-1H-indol-5-yl)picolinaldehyde (Compound 146): LC/MS:m/z=279 [M+H]⁺ (Calc: 278).

Example 7

Synthesis of (S)-1-(6-bromopyridin-2-yl)ethane-1,2-diol (Compound 49)

To a solution of Compound 48 (WO 2012/035421) (2.35 g, 12.77 mmol) int-BuOH (35 mL) and water (35 mL) at 0° C. was added AD-mix-alpha (17.4g, 1.36 g/mmol of vinyl substrate, Sigma-Aldrich). The reaction mixturewas stirred at RT overnight, diluted with water and extracted withEtOAc. The combined organic extracts were washed with brine, dried overMgSO₄, concentrated and the residue purified by flash chromatography(SiO₂, 40-80% EtOAc/hexanes) to give Compound 49 as a white solid (2.30g). Yield 82%. ¹H NMR (400 MHz, CDCl₃): δ 7.61 (t, J=7.6 Hz, 1H), 7.45(d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 4.83 (dd, J=10.0, 5.6 Hz,1H), 3.99-3.94 (m, 1H), 3.81 (pent, J=5.6 Hz, 1H), 3.74 (d, J=5.6 Hz,1H), 2.37 (t, J=6.4 Hz, 1H). LC/MS: m/z=219 [M+H]⁺ (Calc: 218).

In a similar manner, the following compounds were prepared:

(R)-1-(2-(1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)ethane-1,2-diol(Compound 50): ¹H NMR (400 MHz, MeOH-d₄) δ: 9.14 (s, 1H), 8.73 (d, J=5.1Hz, 1H), 8.70 (s, 1H), 8.61 (dd, J=8.7, 1.2 Hz, 1H), 7.95 (q, J=8.7 Hz,4H), 7.87 (d, J=8.6 Hz, 1H), 7.48 (d, J=5.1 Hz, 1H), 4.70 (dd, J=5.7,4.2 Hz, 1H), 3.88 (dd, J=11.2, 4.0 Hz, 1H), 3.74 (dd, J=11.2, 5.9 Hz,1H). LC/MS: m/z=401 [M+H]⁺ (Calc: 400); and

(S)-1-(2-(1-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)ethane-1,2-diol(Compound 51): ¹H NMR (400 MHz, MeOH-d₄) δ: 9.05 (s, 1H), 8.73 (d, J=5.1Hz, 1H), 8.69 (s, 1H), 8.59 (dd, J=8.6, 1.3 Hz, 1H), 7.94 (q, J=8.7 Hz,4H), 7.86 (d, J=8.8 Hz, 1H), 7.47 (d, J=5.3 Hz, 1H), 4.70 (dd, J=5.8,4.1 Hz, 1H), 3.88 (dd, J=11.2, 4.0 Hz, 1H), 3.74 (dd, J=11.2, 5.9 Hz,1H). LC/MS: m/z=401 [M+H]⁺ (Calc: 400).

Example 8 Synthesis of6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide (Compound56)

To a solution of Compound 27 (387 mg, 2.40 mmol) and6-bromopicolinonitrile (Compound 52) (400 mg, 2.19 mmol) in DME (4 mL)and EtOH (4 mL) was added Pd(PPh₃)₂Cl₂ (77 mg, 0.11 mmol) followed by 2Maq. Na₂CO₃ (2.73 mL, 5.46 mmol). The reaction mixture was purged withnitrogen and stirred at 85° C. for 2 h. After cooling to RT, thereaction was diluted with water and extracted with EtOAc (2×). Thecombined organic layers were dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography (SiO₂, 30-50%EtOAc/hexanes) to give Compound 53 as an off-white solid (404 mg). Yield84%. LC/MS: m/z=220 [M+H]⁺ (Calc: 219).

To a solution of Compound 53 (100 mg, 0.46 mmol) in DMF (2 mL) at RT wasadded sodium hydride (60% in mineral oil, 22 mg, 0.55 mmol). Thereaction mixture was stirred for 10 min then1-(bromomethyl)-4-(trifluoromethyl)benzene (Compound 54) (120 mg, 0.50mmol) was added in one portion. The reaction mixture was stirred for anadditional 15 min then quenched with water and extracted with EtOAc(2×). The combined organic layers were washed with water (2×) then driedover MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 30-50% EtOAc/hexanes) to give Compound 55 as awhite solid (142 mg). Yield 82%. LC/MS: m/z=378 [M+H]⁺ (Calc: 377).

To a partial suspension of Compound 55 (134 mg, 0.355 mmol) in EtOH (4mL) and water (0.4 mL) was added hydrido(dimethylphosphinousacid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (23 mg, 0.053mmol, Strem). The reaction mixture was stirred at 85° C. for 1 h duringwhich time all solids had dissolved. The reaction was cooled to RT,directly absorbed onto silica gel and purified by flash chromatography(SiO₂, 30-70% EtOAc/hexanes) to provide Compound 56 as a white solid(114 mg). Yield 81%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.54 (d, J=1.3 Hz,1H), 8.29 (br. s., 1H), 8.14 (dd, J=7.9, 0.7 Hz, 1H), 8.06 (dd, J=8.7,1.7 Hz, 1H), 7.99 (t, J=7.8 Hz, 1H), 7.90 (dd, J=7.5, 0.7 Hz, 1H),7.66-7.73 (m, 3H), 7.60 (d, J=3.3 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.38(d, J=7.9 Hz, 2H), 6.64 (d, J=3.1 Hz, 1H), 5.61 (s, 2H). LC/MS: m/z=396[M+H]⁺ (Calc: 395).

In a similar manner, the following compounds were prepared:

6-(1-((4-(trifluoromethyl)phenyl) sulfonyl)-1H-indol-5-yl)picolinamide(Compound 57): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.60 (s, 1H), 8.28-8.34 (m,2H), 8.24 (d, J=8.1 Hz, 2H), 8.18 (d, J=7.7 Hz, 1H), 7.90-8.10 (m, 6H),7.73 (br. s., 1H), 6.97 (d, J=3.7 Hz, 1H). LC/MS: m/z=446 [M+H]⁺ (Calc:445);

6-(1-(cyclohexylmethyl)-1H-indol-5-yl)picolinamide (Compound 58): ¹H NMR(400 MHz, CDCl₃) δ: 8.30 (d, J=1.5 Hz, 1H), 8.13 (br. s., 1H), 8.11 (dd,J=7.3, 1.1 Hz, 1H), 7.87-8.00 (m, 3H), 7.45 (d, J=8.6 Hz, 1H), 7.15 (d,J=3.1 Hz, 1H), 6.60 (d, J=3.1 Hz, 1H), 5.62 (br. s., 1H), 4.00 (d, J=7.3Hz, 2H), 1.84-1.98 (m, 1H), 1.62-1.79 (m, 5H), 1.14-1.30 (m, 3H),0.95-1.11 (m, 2H). LC/MS: m/z=334 [M+H]⁺ (Calc: 333);

6-(1-(cyclohexylsulfonyl)-1H-indol-5-yl)picolinamide (Compound 59): ¹HNMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H), 8.35 (br. s., 1H), 8.30 (dd,J=8.9, 1.4 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.07 (t, J=7.7 Hz, 1H),7.92-8.00 (m, 2H), 7.75 (br. s., 1H), 7.64 (d, J=3.5 Hz, 1H), 6.92 (d,J=3.5 Hz, 1H), 3.66 (tt, J=11.7, 3.1 Hz, 1H), 1.83 (d, J=11.2 Hz, 2H),1.72 (d, J=13.2 Hz, 2H), 1.55 (d, J=12.5 Hz, 1H), 1.40 (qd, J=12.3, 2.9Hz, 2H), 1.22 (q, J=12.8 Hz, 2H), 1.00-1.14 (m, 1H). LC/MS: m/z=384[M+H]⁺ (Calc: 383);

6-(1-(2-(diethylamino)ethyl)-1H-indol-6-yl)picolinamide (Compound 60):LC/MS: m/z=337 [M+H]⁺ (Calc: 336);

6-(1-(4-fluorobenzyl)-1H-indol-5-yl)picolinamide (Compound 61): ¹H NMR(400 MHz, DMSO-d₆) δ: 8.45 (d, J=1.1 Hz, 1H), 8.22 (br. s., 1H), 8.07(d, J=7.3 Hz, 1H), 7.99 (dd, J=8.7, 1.7 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H),7.81-7.85 (m, 1H), 7.61 (br. s., 1H), 7.46-7.52 (m, 2H), 7.19-7.25 (m,2H), 7.04-7.13 (m, 2H), 6.53 (d, J=3.1 Hz, 1H), 5.40 (s, 2H). LC/MS:m/z=346 [M+H]⁺ (Calc: 345);

6-(1-(4-methylbenzyl)-1H-indol-5-yl)picolinamide (Compound 62): ¹H NMR(400 MHz, DMSO-d₆) δ: 8.57 (d, J=1.5 Hz, 1H), 8.35 (br. s., 1H), 8.19(dd, J=7.9, 0.7 Hz, 1H), 8.10 (dd, J=8.6, 1.8 Hz, 1H), 8.04 (t, J=7.8Hz, 1H), 7.95 (dd, J=7.5, 0.7 Hz, 1H), 7.74 (br. s., 1H), 7.57-7.63 (m,2H), 7.15-7.21 (m, 4H), 6.64 (d, J=3.1 Hz, 1H), 5.48 (s, 2H), 2.30 (s,3H). LC/MS: m/z=342 [M+H]⁺ (Calc: 341);

6-(1-(2-cyclohexylethyl)-1H-indol-5-yl)picolinamide (Compound 63): ¹HNMR (400 MHz, DMSO-d₆) δ: 8.44 (d, J=1.3 Hz, 1H), 8.23 (br. s., 1H),8.08 (dd, J=7.9, 0.7 Hz, 1H), 8.01 (dd, J=8.8, 1.8 Hz, 1H), 7.92 (t,J=7.7 Hz, 1H), 7.83 (dd, J=7.5, 0.7 Hz, 1H), 7.63 (br. s., 1H), 7.47 (d,J=8.6 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 6.47 (d, J=2.9 Hz, 1H), 4.17 (t,J=7.4 Hz, 2H), 1.47-1.73 (m, 7H), 1.01-1.21 (m, 4H), 0.80-0.97 (m, 2H).LC/MS: m/z=348 [M+H]⁺ (Calc: 347);

6-(1-(pyridin-4-ylmethyl)-1H-indol-5-yl)picolinamide (Compound 64): ¹HNMR (400 MHz, DMSO-d₆) δ: 8.64-8.68 (m, 2H), 8.51 (d, J=1.3 Hz, 1H),8.23 (br. s., 1H), 8.08 (dd, J=7.9, 0.7 Hz, 1H), 8.00 (dd, J=8.7, 1.7Hz, 1H), 7.93 (t, J=7.7 Hz, 1H), 7.84 (dd, J=7.5, 0.7 Hz, 1H), 7.63 (br.s., 1H), 7.55 (d, J=3.3 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.38 (d, J=6.4Hz, 2H), 6.63 (d, J=3.1 Hz, 1H), 5.71 (s, 2H). LC/MS: m/z=329 [M+H]⁺(Calc: 328);

6-(1-(2-morpholinoethyl)-1H-indol-5-yl)picolinamide (Compound 65): ¹HNMR (400 MHz, DMSO-d₆) δ: 8.52 (d, J=1.1 Hz, 1H), 8.24 (br. s., 1H),8.07-8.14 (m, 2H), 7.95 (t, J=7.7 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66(br. s., 1H), 7.61 (d, J=8.8 Hz, 1H), 7.43 (d, J=3.1 Hz, 1H), 6.57 (d,J=3.1 Hz, 1H), 4.58 (t, J=7.2 Hz, 2H), 3.02-3.76 (m, 10H). LC/MS:in/z=351 [M+H]⁺ (Calc: 350);

6-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-indol-5-yl)picolinamide(Compound 66): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.58 (d, J=1.3 Hz, 1H), 8.37(br. s., 1H), 8.21 (d, J=7.5 Hz, 1H), 8.17 (dd, J=8.7, 1.7 Hz, 1H), 8.05(t, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 7.75 (br. s., 1H), 7.60 (d, J=8.8Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 6.64 (d, J=3.1 Hz, 1H), 5.35 (s, 2H),2.44 (s, 3H), 2.04 (s, 3H). LC/MS: m/z=347 [M+H]⁺ (Calc: 346);

6-(1-isobutyl-1H-indol-5-yl)picolinamide (Compound 67): ¹H NMR (400 MHz,DMSO-d₆) δ: 8.44 (d, J=1.3 Hz, 1H), 8.24 (br. s., 1H), 8.07 (dd, J=7.9,0.7 Hz, 1H), 7.99 (dd, J=8.7, 1.7 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H),7.81-7.86 (m, 1H), 7.63 (br. s., 1H), 7.50 (d, J=8.6 Hz, 1H), 7.31-7.37(m, 1H), 6.47 (d, J=3.1 Hz, 1H), 3.95 (d, J=7.3 Hz, 2H), 2.07 (dquin,J=13.6, 6.8 Hz, 1H), 0.79 (d, J=6.6 Hz, 6H). LC/MS: m/z=294 [M+H]⁺(Calc: 293);

6-(1-((2-methylthiazol-4-yl)methyl)-1H-indol-5-yl)picolinamide (Compound68): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.45 (d, J=1.3 Hz, 1H), 8.24 (br. s.,1H), 8.05-8.10 (m, 1H), 8.01 (dd, J=8.7, 1.7 Hz, 1H), 7.92 (t, J=7.7 Hz,1H), 7.83 (dd, J=7.6, 0.8 Hz, 1H), 7.62 (br. s., 1H), 7.57 (d, J=8.8 Hz,1H), 7.44 (d, J=3.1 Hz, 1H), 7.23 (s, 1H), 6.50 (d, J=3.1 Hz, 1H), 5.40(s, 2H), 2.53 (s, 3H). LC/MS: m/z=349 [M+H]⁺ (Calc: 348);

6-(3-formyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinonitrile(Compound 69): LC/MS: m/z=406 [M+H]⁺ (Calc: 405); and

6-(3-formyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 70): LC/MS: m/z=424 [M+H]⁺ (Calc: 423).

Example 9 Synthesis of6-(1-methyl-1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide(Compound 75)

To a solution of 6-bromopicolinic acid (Compound 71) (1.00 g, 4.95 mmol)and 4-(trifluoromethyl)aniline (Compound 72) (0.88 g, 5.45 mmol) in DMF(10 mL) were added HATU (1.98 g, 5.20 mmol) and DIPEA (1.3 mL, 7.43mmol). The bright yellow reaction mixture was stirred at RT overnightthen cooled to 0° C. and quenched with water (40 mL). The reaction wasstirred vigorously at 0° C. for 20 min then the resultant precipitatewas collected via filtration and rinsed with water. The filter cake wasdissolved in EtOAc and washed with water and brine. The organic layerwas dried over MgSO₄ and concentrated to a beige solid which waspurified by flash chromatography (SiO₂, 10-30% EtOAc/hexanes) to affordCompound 73 as a pale yellow solid (1.55 g). Yield 91%. LC/MS:m/z=345/347 [M+H]⁺ (Calc: 345).

To a solution of (1-methyl-1H-indol-5-yl)boronic acid (Compound 74) (91mg, 0.52 mmol) and Compound 73 (150 mg, 0.44 mmol) in DME (1.5 mL) andEtOH (1.5 mL) was added Pd(PPh₃)₂Cl₂ (15 mg, 0.022 mmol) followed by 2Maq. Na₂CO₃ (0.54 mL, 1.08 mmol). The reaction mixture was purged withnitrogen and stirred at 85° C. for 1 h. After cooling to RT, thereaction was diluted with water and extracted with EtOAc (2×). Thecombined organic layers were dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography (SiO₂, 10-30%EtOAc/hexanes) to give Compound 75 as a beige solid (135 mg). Yield 79%.¹H NMR (400 MHz, DMSO-d₆) δ: 10.85 (s, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.27(d, J=7.9 Hz, 1H), 8.16-8.23 (m, 3H), 8.10 (t, J=7.7 Hz, 1H), 8.04 (d,J=7.5 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (d,J=3.1 Hz, 1H), 6.58 (d, J=2.9 Hz, 1H), 3.86 (s, 3H). LC/MS: m/z=396[M+H]⁺ (Calc: 395).

In a similar manner, the following compounds were prepared:

N-cyclohexyl-6-(1H-indol-5-yl)picolinamide (Compound 76): ¹H NMR (400MHz, DMSO-d₆) δ: 11.25 (br. s., 1H), 8.40-8.48 (m, 2H), 8.13 (d, J=7.9Hz, 1H), 7.96-8.05 (m, 2H), 7.90 (d, J=7.0 Hz, 1H), 7.52 (d, J=8.6 Hz,1H), 7.42 (t, J=2.6 Hz, 1H), 6.56 (br. s., 1H), 3.76-3.95 (m, 1H),1.83-1.92 (m, 2H), 1.71-1.81 (m, 2H), 1.63 (d, J=12.5 Hz, 1H), 1.45-1.57(m, 2H), 1.29-1.43 (m, 2H), 1.14-1.28 (m, 1H). LC/MS: m/z=320 [M+H]⁺(Calc: 319);

6-(1H-indazol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide (Compound77): ¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), 10.86 (s, 1H), 8.82 (s,1H), 8.42 (d, J=8.8 Hz, 1H), 8.31 (d, J=7.7 Hz, 1H), 8.06-8.25 (m, 5H),7.79 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.8 Hz, 1H). LC/MS: m/z=383 [M+H]⁺(Calc: 382);

(S)-2-(1H-indol-5-yl)-6-((2-oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)-phenyl)pyrimidine-4-carboxamide(Compound 78): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.65 (s, 1H), 8.18 (m, 1H),7.90 (m, 2H), 7.54 (m, 2H), 7.40 (m, 1H), 7.20 (s, 1H), 7.05 (s, 1H),6.50 (s, 1H), 4.95 (m, 1H), 3.40 (m, 2H), 2.60 (m, 1H), 2.20 (m, 1H).LC/MS: m/z=481 [M+H]⁺ (Calc: 480);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(benzofuran-5-yl)-N-(4-(trifluoro-methyl)phenyl)pyrimidine-4-carboxamide (Compound 79): ¹H NMR (400 MHz, MeOH-d₄) δ:8.90 (s, 1H), 8.60 (d, J=7.20 Hz, 1H), 8.10 (d, J=7.20 Hz, 2H), 7.80 (s,1H), 7.70 (m, 2H), 7.60 (d, J=7.20 Hz, 1H), 7.25 (s, 1H), 6.98 (s, 1H),4.70 (m, 1H), 1.60 (d, J=6.80 Hz, 3H). LC/MS: m/z=470 [M+H]⁺ (Calc:469);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1H-indol-5-yl)-N-(4-(trifluoro-methyl)phenyl)pyrimidine-4-carboxamide (Compound 80): ¹H NMR (400 MHz, MeOH-d₄) δ:8.85 (s, 1H), 8.40 (d, J=7.20 Hz, 1H), 8.10 (d, J=7.20 Hz, 2H), 7.70 (m,2H), 7.45 (m, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 6.60 (s, 1H), 4.70 (m,1H), 1.60 (d, J=6.80 Hz. 3H). LC/MS: m/z=469 [M+H]⁺ (Calc: 468); and

6-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide (Compound81): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.50 (s, 1H), 8.10-8.25 (m, 3H),8.00-8.15 (m, 3H), 7.85 (s, 1H), 7.60-7.78 (m, 3H), 7.05 (s, 1H). LC/MS:m/z=383 [M+H]⁺ (Calc: 382).

Example 10 Synthesis ofN-(cyclohexylmethyl)-6-(1H-indol-5-yl)picolinamide (Compound 83)

Compound 39 (57 mg, 0.504 mmol) was added to a mixture of Compound 82(100 mg, 0.420 mmol), HATU (192 mg, 0.504 mmol) and DIPEA (0.281 mL,1.51 mmol) in DMF (2 mL). The mixture was stirred at RT overnight,quenched with water and concentrated. The residue was purified by flashchromatography (SiO₂, 0-100%, EtOAc/hexanes) to give Compound 83 as awhite solid (105 mg). Yield 75%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.17 (br.s., 1H), 8.76 (t, J=6.3 Hz, 1H), 8.42 (s, 1H), 8.07 (d, J=7.5 Hz, 1H),7.98 (dd, J=8.6, 1.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.3 Hz,1H), 7.43 (d, J=8.6 Hz, 1H), 7.34 (t, J=2.6 Hz, 1H), 6.48 (br. s., 1H),3.17 (t, J=6.6 Hz, 2H), 1.49-1.70 (m, 6H), 1.03-1.20 (m, 3H), 0.84-0.97(m, 2H). LC/MS: m/z=334 [M+H]⁺ (Calc: 333).

In a similar manner, the following compounds were prepared:

(6-(1H-indol-5-yl)pyridin-2-yl)(pyrrolidin-1-yl)methanone (Compound 84):¹H NMR (400 MHz, DMSO-d₆) δ: 11.18 (br. s., 1H), 8.24 (s, 1H), 7.95-7.99(m, 1H), 7.85-7.91 (m, 1H), 7.82 (dd, J=8.6, 1.5 Hz, 1H), 7.52 (dd,J=7.5, 0.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.34 (t, J=2.6 Hz, 1H), 6.48(t, J=2.0 Hz, 1H), 3.66-3.75 (m, 2H), 3.49 (t, J=6.9 Hz, 2H), 1.78-1.88(m, 4H). LC/MS: m/z=292 [M+H]⁺ (Calc: 291);

N-cyclopentyl-6-(1H-indol-5-yl)picolinamide (Compound 85): ¹H NMR (400MHz, DMSO-d₆) δ: 11.18 (br. s., 1H), 8.41-8.48 (m, 1H), 8.37 (d, J=0.7Hz, 1H), 8.05 (d, J=0.7 Hz, 1H), 7.89-7.98 (m, 2H), 7.83 (d, J=0.9 Hz,1H), 7.45 (d, J=8.6 Hz, 1H), 7.34 (t, J=2.8 Hz, 1H), 6.46-6.52 (m, 1H),4.17-4.30 (m, 1H), 1.82-1.95 (m, 2H), 1.46-1.75 (m, 6H). LC/MS: m/z=306[M+H]⁺ (Calc: 305);

(6-(1H-indol-5-yl)pyridin-2-yl)(2,6-dimethylmorpholino)methanone(Compound 86): ¹H NMR (400 MHz, DMSO-d₆) δ: 11.18 (br. s., 1H), 8.24 (s,1H), 7.95-8.01 (m, 1H), 7.86-7.92 (m, 1H), 7.80 (dd, J=8.6, 1.5 Hz, 1H),7.43 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.34 (t, J=2.6 Hz, 1H),6.47 (t, J=2.0 Hz, 1H), 4.38 (d, J=12.8 Hz, 1H), 3.83 (d, J=13.0 Hz,1H), 3.52-3.68 (m, 2H), 2.79 (dd, J=13.0, 10.6 Hz, 1H), 2.49 (dd,J=12.9, 10.9 Hz, 1H), 1.12 (d, J=6.2 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H).LC/MS: m/z=336 [M+H]⁺ (Calc: 335);

6-(1H-indol-5-yl)-N-(1H-tetrazol-5-yl)picolinamide (Compound 87): ¹H NMR(400 MHz, MeOH-d₄) δ: 8.38 (d, J=1.1 Hz, 1H), 8.11 (dd, J=7.9, 0.9 Hz,1H), 8.03-8.07 (m, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.94 (dd, J=8.8, 1.3 Hz,1H), 7.44 (d, J=8.6 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 6.51 (dd, J=3.1,0.7 Hz, 1H). LC/MS: m/z=306 [M+H]⁺ (Calc: 305); and

(S)-6-(1H-indol-5-yl)-4-((2-oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)picolinamide (Compound 88): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.41 (d, J=2.0Hz, 1H), 8.33 (dd, J=7.7, 1.5 Hz, 2H), 7.97 (d, J=8.6 Hz, 2H), 7.89 (dd,J=8.6, 1.5 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H),7.22-7.26 (m, 1H), 6.52 (d, J=2.6 Hz, 1H), 4.28 (dd, J=11.2, 8.8 Hz,1H), 4.07-4.16 (m, 1H), 3.99 (td, J=9.9, 6.8 Hz, 1H), 2.63-2.73 (m, 1H),2.07-2.21 (m, 1H). LC/MS: m/z=480 [M+H]⁺ (Calc: 479).

Example 11 Synthesis of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole(Compound 91)

To a solution of 5-bromo-1H-indole (Compound 89) (2.50 g, 12.75 mmol) inDMF (30 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.61g, 15.30 mmol). The reaction mixture was warmed to RT and stirred for 20min then cooled to 0° C. and Compound 54 (3.35 g, 14.03 mmol) was addedin one portion. The reaction mixture was stirred at RT for 1 h thencarefully quenched with water and extracted with EtOAc (2×). Thecombined organic layers were washed with water (3×) and brine then driedover MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-10% EtOAc/hexanes) to provide Compound 90 as anoff-white solid (4.49 g). Yield 99%. LC/MS: m/z=355 [M+H]⁺ (Calc: 354).

To a solution of Compound 90 (1.50 g, 4.24 mmol), Compound 19 (1.13 g,4.45 mmol), and potassium acetate (1.25 g, 12.71 mmol) in 1,4-dioxane(20 mL) was added Pd(dppf)Cl₂ DCM adduct (0.173 g, 0.21 mmol). Thereaction was heated at 90° C. overnight then cooled to RT, quenched withwater and extracted with EtOAc (2×). The combined organics were driedover MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-15% EtOAc/hexanes) to give Compound 91 as anoff-white solid (1.08 g). Yield 64%. LC/MS: m/z=402 [M+H]⁺ (Calc: 401).

In a similar manner, the following compounds were prepared:

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine(Compound 92): LC/MS: m/z=403 [M+H]⁺ (Calc: 402);

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole(Compound 93): LC/MS: m/z=403 [M+H]⁺ (Calc: 402);

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(trifluoromethyl)benzyl)-2H-indazole(Compound 94): LC/MS: m/z=403 [M+H]⁺ (Calc: 402);

1-(cyclohexylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(Compound 95): LC/MS: m/z=340 [M+H]⁺ (Calc: 339);

1-(piperidin-1-ylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(Compound 96): LC/MS: m/z=391 [M+H]⁺ (Calc: 390);

1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(Compound 97): LC/MS: m/z=298 [M+H]⁺ (Calc: 297);

1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(Compound 98): LC/MS: m/z=300 [M+H]⁺ (Calc: 299); and1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(Compound 99): LC/MS: m/z=301 [M+H]⁺ (Calc: 300).

Example 12 Synthesis of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole(Compound 104)

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (Compound 13) (1.20 g,5.45 mmol) in THF (10 mL) was added K₂CO₃ (1.13 g, 8.18 mmol) followedby a solution of 4-(trifluoromethyl)benzylamine (Compound 100) (1.05 g,6.00 mmol) in THF (1 mL). The bright orange-yellow reaction mixture wasstirred at RT overnight then quenched with water and extracted withEtOAc (3×). The combined organics were dried over MgSO₄ andconcentrated. The residue was triturated with pet ether then dried underhigh vacuum to provide Compound 101 as a bright orange solid (2.00 g).Yield 98%. LC/MS: m/z=375/377 [M+H]⁺ (Calc: 375).

To a partial suspension of Compound 101 (2.00 g, 5.33 mmol) in EtOH (25mL) and THF (2.5 mL) was added AcOH (1.53 mL, 26.7 mmol) followed byiron powder (0.89 g, 16.0 mmol) and finally water (2.5 mL). Theheterogeneous reaction mixture was stirred at 40° C. for 4 h then cooledto RT, quenched with satd. NaHCO₃ and extracted with DCM (3×). Thecombined organic layers were dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography (SiO₂, 10-20%EtOAc/hexanes) to isolate Compound 102 as a light yellow solid (0.94 g).Yield 51%. LC/MS: m/z=345/347 [M+H]⁺ (Calc: 345).

To Compound 102 (930 mg, 2.69 mmol) was added formic acid (5.08 mL, 135mmol) and the resultant maroon solution was stirred at 100° C. for 30min. The reaction was cooled to RT and carefully poured into satd.NaHCO₃. The mixture was extracted with EtOAc (3×). The combined organicswere washed with satd. NaHCO₃ then dried over MgSO₄ and concentrated.The residue was purified by flash chromatography (SiO₂, 50-80%EtOAc/hexanes) to afford Compound 103 as a yellow solid (862 mg). Yield90%. LC/MS: m/z=355/357 [M+H]⁺ (Calc: 355).

To a solution of Compound 103 (860 mg, 2.42 mmol), Compound 19 (676 mg,2.66 mmol), and potassium acetate (713 mg, 7.26 mmol) in 1,4-dioxane (10mL) was added Pd(dppf)Cl₂ DCM adduct (99 mg, 0.121 mmol). The reactionwas heated at 90° C. overnight then cooled to RT, quenched with waterand extracted with EtOAc (2×). The combined organics were dried overMgSO₄ and concentrated. The residue was purified by flash chromatography(SiO₂, 40-100% EtOAc/hexanes) to give Compound 104 as a beige solid (622mg). Yield 64%. LC/MS: m/z=403 [M+H]⁺ (Calc: 402).

Example 13 Synthesis of6-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-5-yl)picolinamide (Compound105)

To a solution of Compound 93 (147 mg, 0.37 mmol) and Compound 28 (70 mg,0.35 mmol) in DME (2.5 mL) and EtOH (1.5 mL) was added Pd(PPh₃)₂Cl₂ (12mg, 0.017 mmol) followed by 2M aq. Na₂CO₃ (0.52 mL, 1.05 mmol). Thereaction mixture was purged with nitrogen and stirred at 85° C. for 2 h.After cooling to RT, the mixture was diluted with water and extractedwith EtOAc (2×). The combined organic extracts were dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂,50-80% EtOAc/hexanes) to give Compound 105 as a white solid (103 mg).Yield 75%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.65 (d, J=0.7 Hz, 1H), 8.30(dd, J=8.8, 1.8 Hz, 1H), 8.24 (s, 1H), 8.14 (dd, J=7.0, 1.8 Hz, 1H),8.00-8.07 (m, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.39(d, J=8.1 Hz, 2H), 5.80 (s, 2H). LC/MS: m/z=397 [M+H]⁺ (Calc: 396).

In a similar manner, the following compounds were prepared:

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 106): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.95 (d, J=2.0 Hz, 1H),8.66 (d, J=2.0 Hz, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H),7.62 (d, J=8.1 Hz, 2H), 7.49-7.55 (m, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.70(d, J=3.5 Hz, 1H), 5.66 (s, 2H), 4.84-4.89 (m, 1H, obscured by water),3.99 (dd, J=11.2, 4.2 Hz, 1H), 3.81 (dd, J=11.2, 6.7 Hz, 1H). LC/MS:m/z=414 [M+H]⁺ (Calc: 413);

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 107): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.48 (s, 1H), 8.22 (s, 1H),8.16 (dd, J=8.8, 1.5 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.81 (d, J=7.5 Hz,1H), 7.60-7.68 (m, 3H), 7.50 (d, J=7.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H),5.79 (s, 2H), 4.85 (dd, J=6.6, 4.2 Hz, 1H), 3.97 (dd, J=11.2, 4.2 Hz,1H), 3.80 (dd, J=11.2, 6.6 Hz, 1H). LC/MS: m/z=414 [M+H]⁺ (Calc: 413);

(S)-1-(6-(2-(4-(trifluoromethyl)benzyl)-2H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 108): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.49 (s, 1H), 8.41 (s, 1H),8.07 (dd, J=9.0, 1.7 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.80 (d, J=7.5 Hz,1H), 7.72 (d, J=9.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.46-7.51 (m, 3H),5.78 (s, 2H), 4.86 (dd, J=6.6, 4.2 Hz, 1H), 3.98 (dd, J=11.2, 4.2 Hz,1H), 3.80 (dd, J=11.2, 6.6 Hz, 1H). LC/MS: m/z=414 [M+H]⁺ (Calc: 413);

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 109): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.15 (d, J=0.9 Hz, 1H),7.68-7.75 (m, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.33(d, J=7.8 Hz, 1H), 7.25-7.31 (m, 2H), 7.20 (d, J=8.1 Hz, 2H), 6.55 (d,J=3.1 Hz, 1H), 5.44 (s, 2H), 4.73 (dd, J=6.6, 4.2 Hz, 1H), 3.85 (dd,J=11.2, 4.2 Hz, 1H), 3.67 (dd, J=11.2, 6.6 Hz, 1H). LC/MS: m/z=413[M+H]⁺ (Calc: 412);

(S)-1-(6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 110): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.41 (s, 1H), 8.38 (d,J=0.7 Hz, 1H), 8.01 (dd, J=8.6, 1.3 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H),7.79 (d, J=7.7 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.44-7.55 (m, 4H), 5.68(s, 2H), 4.85 (dd, J=6.6, 4.2 Hz, 1H), 3.97 (dd, J=11.2, 4.2 Hz, 1H),3.80 (dd, J=11.2, 6.6 Hz, 1H). LC/MS: m/z=414 [M+H]⁺ (Calc: 413);

(S)-1-(6-(1-(piperidin-1-ylsulfonyl)-1H-indol-5-yl)pyridin-2-yl)ethane-1,2-diol(Compound 111): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.30 (s, 1H), 7.98-8.07 (m,2H), 7.88 (t, J=7.7 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.59 (d, J=3.5 Hz,1H), 7.50 (d, J=7.5 Hz, 1H), 6.81 (d, J=3.5 Hz, 1H), 4.84-4.88 (m, 1H),3.98 (dd, J=11.2, 4.2 Hz, 1H), 3.81 (dd, J=11.2, 6.8 Hz, 1H), 3.22-3.27(m, 4H), 1.48-1.55 (m, 4H), 1.38-1.46 (m, 2H). LC/MS: m/z=402 [M+H]⁺(Calc: 401);

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)pyrimidine-4-carboxamide(Compound 112): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.82 (d, J=1.1 Hz, 1H),8.34 (dd, J=8.8, 1.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.36 (d, J=3.1 Hz,1H), 7.29-7.35 (m, 3H), 7.11 (s, 1H), 6.67 (d, J=3.1 Hz, 1H), 5.54 (s,2H), 4.64 (br. s., 1H), 1.55 (d, J=7.3 Hz, 3H). LC/MS: m/z=483 [M+H]⁺(Calc: 482); and

(S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(1-(cyclohexylmethyl)-1H-indol-5-yl)pyrimidine-4-carboxamide(Compound 113): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.77 (d, J=0.7 Hz, 1H),8.36 (dd, J=8.7, 1.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.21 (d, J=3.1 Hz,1H), 7.10 (s, 1H), 6.55 (d, J=3.1 Hz, 1H), 4.66 (br. s., 1H), 4.03 (d,J=7.3 Hz, 2H), 1.83-1.96 (m, 1H), 1.58-1.78 (m, 5H), 1.56 (d, J=7.0 Hz,3H), 1.16-1.32 (m, 3H), 0.99-1.12 (m, 2H). LC/MS: m/z=421 [M+H]⁺ (Calc:420).

Example 14 Synthesis of(R)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinonitrile(Compound 119) and(R)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 120)

To a solution of Compound 91 (548 mg, 1.37 mmol) and4,6-dichloropicolinonitrile (Compound 114) (225 mg, 1.30 mmol) in DME (6mL) and EtOH (2 mL) was added 2M aq. Na₂CO₃ (1.95 mL, 3.90 mmol)followed by Pd(PPh₃)₂Cl₂ (46 mg, 0.065 mmol). The reaction mixture waspurged with nitrogen and stirred at 40° C. for 1 h. After cooling to RT,the reaction was diluted with water and extracted with EtOAc (2×). Thecombined organics were dried over MgSO4 and concentrated. The reactionwas repeated on the same exact scale except heating at 85° C. for 1.5 h.After similar workup, the residue was combined with that from the firstreaction and purified by flash chromatography (SiO₂, 0-20%EtOAc/hexanes) to afford first Compound 115 as a white solid (502 mg;Yield 47%) followed by Compound 116 as a light brown solid (248 mg;Yield 23%). Compound 115: LC/MS: m/z=412 [M+H]⁺ (Calc: 411). Compound116: LC/MS: m/z=412 [M+H]⁺ (Calc: 411).

In a 15 mL pressure tube, Compound 115 (480 mg, 1.16 mmol) was dissolvedin THF (5 mL). Then was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Compound 117) (0.26 mL,1.52 mmol), TBAF (1M in THF, 2.33 mL, 2.33 mmol), and Pd(dppf)Cl₂ DCMadduct (48 mg, 0.058 mmol). The reaction was purged with nitrogen thenthe tube was sealed and stirred at 85° C. for 2 h. After cooling to RTthe mixture was partioned between water and EtOAc. The aqueous layer wasextracted with EtOAc. The combined organics were dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂,0-20% EtOAc/hexanes) to give Compound 118 as a white solid (367 mg).Yield 78%. LC/MS: m/z=404 [M+H]⁺ (Calc: 403).

To a partial suspension of Compound 118 (175 mg, 0.43 mmol) in t-BuOH (6ml), water (6 mL), and i-PrOH (2 ml) was added AD-mix-beta (600 mg; 1.4g/mmol of vinyl substrate, Sigma-Aldrich). The reaction mixture wasstirred vigorously at RT for 64 h then diluted with water and extractedwith EtOAc (2×). The combined organic extracts were dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂,30-80% EtOAc/hexanes) to provide Compound 119 as an off-white solid (142mg). Yield 75%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.35 (d, J=1.3 Hz, 1H),8.17 (s, 1H), 7.90 (dd, J=8.8, 1.7 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=8.1Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.32 (d, J=8.1Hz, 2H), 6.70 (d, J=3.3 Hz, 1H), 5.56 (s, 2H), 4.83 (t, J=5.4 Hz, 1H),3.75 (dd, J=5.4, 1.8 Hz, 2H). LC/MS: m/z=438 [M+H]⁺ (Calc: 437).

To a partial suspension of Compound 119 (100 mg, 0.23 mmol) in EtOH (5mL) and water (0.5 mL) was added hydrido(dimethylphosphinousacid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (10 mg, 0.023mmol, Strem). The reaction mixture was stirred at 85° C. for 30 minduring which time all solids had dissolved. The reaction was cooled toRT and concentrated. The residue was absorbed onto silica gel andpurified by flash chromatography (SiO₂, 50-100% EtOAc/hexanes) toisolate Compound 120 as a white solid (75 mg). Yield 72%. ¹H NMR (400MHz, MeOH-d₄) δ: 8.44 (d, J=1.3 Hz, 1H), 8.11 (s, 1H), 8.04 (d, J=0.7Hz, 1H), 7.99 (dd, J=8.6, 1.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.42 (d,J=8.6 Hz, 1H), 7.39 (d, J=3.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.70 (d,J=3.1 Hz, 1H), 5.56 (s, 2H), 4.83-4.88 (m, 1H), 3.78 (dd, J=11.4, 4.8Hz, 1H), 3.73 (dd, J=11.4, 6.6 Hz, 1H). LC/MS: m/z=456 [M+H]⁺ (Calc:455).

In a similar manner, the following compounds were prepared:

(S)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 121): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.44 (s, 1H), 8.11 (s, 1H),8.04 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.42 (d,J=8.6 Hz, 1H), 7.39 (d, J=3.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.69 (d,J=3.1 Hz, 1H), 5.56 (s, 2H), 4.83-4.86 (m, 1H), 3.78 (dd, J=11.2, 4.8Hz, 1H), 3.73 (dd, J=11.2, 6.6 Hz, 1H). LC/MS: m/z=456 [M+H]⁺ (Calc:455);

(R)-6-(1,2-dihydroxyethyl)-4-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 122): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.34 (d, J=1.5 Hz, 1H),8.09 (d, J=1.5 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.57-7.65 (m, 3H), 7.46(d, J=8.6 Hz, 1H), 7.42 (d, J=3.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.69(d, J=3.1 Hz, 1H), 5.57 (s, 2H), 4.90 (dd, J=6.2, 4.6 Hz, 1H), 3.94 (dd,J=11.4, 4.6 Hz, 1H), 3.84 (dd, J=11.4, 6.2 Hz, 1H). LC/MS: m/z=456[M+H]⁺ (Calc: 455);

(S)-6-(1,2-dihydroxyethyl)-4-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 123): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.34 (d, J=1.5 Hz, 1H),8.09 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.56-7.66 (m, 3H), 7.46(d, J=8.8 Hz, 1H), 7.42 (d, J=3.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.69(d, J=3.1 Hz, 1H), 5.56 (s, 2H), 4.88-4.91 (m, 1H), 3.94 (dd, J=11.2,4.6 Hz, 1H), 3.84 (dd, J=11.2, 6.4 Hz, 1H). LC/MS: m/z=456 [M+H]⁺ (Calc:455);

(S)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide(Compound 124): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.41 (d, J=1.3 Hz, 1H),8.19-8.24 (m, 1H), 8.00 (s, 1H), 7.97 (dd, J=8.6, 1.5 Hz, 1H), 7.86 (s,1H), 7.59 (br. s., 1H), 7.50 (d, J=8.6 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H),6.48 (d, J=3.1 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 3.96 (d, J=7.5 Hz, 2H),3.45-3.56 (m, 2H), 2.08 (dquin, J=13.6, 6.8 Hz, 1H), 0.80 (d, J=6.6 Hz,6H). LC/MS: m/z=354 [M+H]⁺ (Calc: 353);

(R)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide(Compound 125): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.48 (d, J=1.3 Hz, 1H),8.28 (br. s., 1H), 8.07 (s, 1H), 8.04 (dd, J=8.7, 1.7 Hz, 1H), 7.93 (s,1H), 7.66 (br. s., 1H), 7.57 (d, J=8.8 Hz, 1H), 7.41 (d, J=3.1 Hz, 1H),6.55 (d, J=2.9 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.03 (d, J=7.3 Hz, 2H),3.52-3.63 (m, 2H), 2.08-2.22 (m, 1H), 0.87 (d, J=6.6 Hz, 6H). LC/MS:m/z=354 [M+H]⁺ (Calc: 353); and

(S)-6-(1,2-dihydroxyethyl)-4-(1-isobutyl-1H-indol-5-yl)picolinamide(Compound 126): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (br. s., 1H), 8.17 (d,J=1.8 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.63 (br.s., 1H), 7.57-7.61 (m, 1H), 7.51-7.56 (m, 1H), 7.38 (d, J=3.1 Hz, 1H),6.51 (d, J=3.1 Hz, 1H), 4.67 (t, J=5.4 Hz, 1H), 3.96 (d, J=7.3 Hz, 2H),3.65-3.73 (m, 1H), 3.56-3.63 (m, 1H), 2.08 (dquin, J=13.6, 6.8 Hz, 1H),0.80 (d, J=6.6 Hz, 6H). LC/MS: m/z=354 [M+H]⁺ (Calc: 353).

Example 15 Synthesis of TFA salt of6-(1-methyl-3-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)picolinamide(Compound 129)

NBS (1.50 g, 8.8 mmol) was added to a solution of Compound 34 (2.00 g,8.0 mmol) in DCM (100 mL) at 0° C. over 30 min After the addition wascomplete, the mixture was stirred at 0° C. for an additional 10 min andfiltered through Na₂SO₄, washing the filter cake with DCM. The filtratewas washed with satd. aq. Na₂SO₃, brine and concentrated to giveCompound 127 as a brown solid that was used in the next step withoutfurther purification (1.30 g). Yield 45%. LC/MS: m/z=330/332 [M+H]⁺(Calc: 330).

A mixture of Compound 127 (0.10 g, 0.3 mmol), Compound 128 (0.0855 g,0.45 mmol), Cs₂CO₃ (0.130 g, 0.45 mmol) and Pd(P(o-tol)₃)₂Cl₂ (0.0215 g,0.03 mmol) in 2:2:1 DME/EtOH/water (5 mL) was flushed with argon thenheated in a microwave reactor at 125° C. for 40 min After cooling to RTthe mixture was diluted with water and extracted with EtOAc. Thecombined organic extracts were dried over MgSO₄ and concentrated. Theresidue was purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA inwater/0.1% TFA in ACN) to afford Compound 129 TFA salt as a yellow solid(80 mg). Yield 67%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.58 (d, J=1.3 Hz, 1H),8.12-8.21 (m, 3H), 8.08 (d, J=7.9 Hz, 1H), 7.82-8.01 (m, 4H), 7.49-7.71(m, 4H), 3.85 (s, 3H). LC/MS: m/z=396 [M+H]⁺ (Calc: 395).

In a similar manner, the following compounds were prepared:

6-(1-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)picolinamide(Compound 130): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.60 (d, J=1.3 Hz, 1H),8.14-8.28 (m, 3H), 7.91-8.00 (m, 3H), 7.84-7.90 (m, 2H), 7.72 (d, J=8.4Hz, 2H), 7.62 (br. s., 1H), 7.59 (d, J=8.8 Hz, 1H), 3.86 (s, 3H). LC/MS:m/z=396 [M+H]⁺ (Calc: 395); and

6-(1-(2-(diethylamino)ethyl)-3-(4-fluorophenyl)-1H-indol-6-yl)picolinamide(Compound 131): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 8.33 (br. s.,1H), 8.23 (d, J=7.9 Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.89-7.97 (m, 2H),7.81 (s, 1H), 7.70 (dd, J=8.7, 5.6 Hz, 3H), 7.26 (t, J=8.8 Hz, 2H), 4.42(t, J=6.2 Hz, 2H), 2.82 (br. s., 2H), 2.5-2.6 (m, 4H), 0.89 (t, J=6.9Hz, 6H). LC/MS: m/z=431 [M+H]⁺ (Calc: 430).

Example 16 Synthesis of TFA salt of6-amino-2-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide(Compound 138)

To a solution of Compound 8 (1.04 g, 5.0 mmol) and DIPEA (1.04 mL) inTHF (5 mL) at 0° C. was added Compound 132 (0.92 g, 5.5 mmol). Themixture was warmed to RT and stirred overnight. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organicextracts were dried over Na₂SO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂, 0-80% EtOAc/DCM) to giveCompound 133 as a white solid (1.5 g). Yield 89%. LC/MS: m/z=338 [M+H]⁺(Calc: 337).

Compound 133 (1.00 g, 2.96 mmol) was dissolved in 10:3 MeOH/water (13mL) and NaOH (0.47 g, 11.84 mmol) was added. The resulting mixture wasstirred at 40° C. for 1 h. The mixture was cooled to RT andconcentrated. Water (20 mL) was added, the mixture cooled to 0° C. andthe pH adjusted to 4 using conc. HCl. The resulting solid was collectedto give Compound 134 as an off white solid (0.70 g). Yield 73%. LC/MS:m/z=324 [M+H]⁺ (Calc: 323).

A mixture of Compound 134 (0.70 g, 2.16 mmol), Compound 72 (0.35 g, 2.16mmol) and HATU (0.90 g, 2.38 mmol) in DMF (4 mL) was cooled to 0° C. andDIPEA (0.45 mL, 2.59 mmol) was added dropwise. The reaction mixture waswarmed to RT and stirred overnight. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic extracts weredried over Na₂SO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-20% MeOH/DCM) to give Compound 135 as an offwhite solid (0.70 g). Yield 69%. LC/MS: m/z=467 [M+H]⁺ (Calc: 466).

A mixture of Compound 135 (0.70 g, 1.5 mmol), Compound 136 (243 mg, 1.5mmol), K₂CO₃ (311 mg, 2.25 mmol) and Pd(PPh₃)₂Cl₂ (53 mg, 0.075 mmol)was suspended in 2:1:2 DME/EtOH/water (10 mL), purged with argon for 2min and then heated at 90° C. for 14 h. The mixture was cooled to RT,diluted with water and extracted with DCM. The organic extracts weredried over Na₂SO₄ and concentrated. The residue was purified by flashchromatography (SiO₂, 0-20% MeOH/DCM) to give Compound 137 as an offwhite solid (500 mg). Yield 61%. LC/MS: m/z=549 [M+H]⁺ (Calc: 548).

A solution of Compound 137 (100 mg, 0.182 mmol) in TFA (5 mL) was heatedat 60° C. for 4 h. The mixture was cooled to RT and concentrated. Theresidue was purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA inACN/0.1% TFA in water) to give Compound 138 TFA salt as a white solid(50 mg). Yield 69%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.80 (s, 1H), 8.50 (d,J=7.20 Hz, 1H), 8.05 (d, J=7.20 Hz, 2H), 7.80 (s, 1H), 7.70 (d, J=7.20Hz, 2H), 7.60 (d, J=7.20 Hz, 1H), 7.20 (s, 1H), 6.95 (s, 1H). LC/MS:m/z=399 [M+H]⁺ (Calc: 398).

Example 17 Synthesis of5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxylicacid (Compound 139) and5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamide(Compound 140)

NaClO₂ (892 mg, 9.87 mmol) was added to a mixture of Compound 46 (202mg, 0.493 mmol) and NaH₂PO₄ (1.18 g, 9.87 mmol) in 1:1 THF/water (4 mL).The mixture was stirred for 30 min and DCM and 20% aq. HCl (10 mL each)were added. The layers were separated and the aqueous layer wasextracted with DCM. The organic extracts were combined, washed withwater, dried over MgSO₄ and concentrated. The residue was purified byflash chromatography (SiO₂, 0-80% MeOH/DCM) to give Compound 139 as anoff-white solid (134 mg). Yield 64%. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.14(br. s., 1H), 11.99 (d, J=2.0 Hz, 1H), 10.84 (s, 1H), 8.80 (d, J=1.3 Hz,1H), 8.32 (dd, J=8.6, 1.8 Hz, 1H), 8.21-8.26 (m, 1H), 8.12-8.18 (m, 3H),8.05-8.11 (m, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 1H).LC/MS: m/z=448 [M+Na]⁺ (Calc: 425).

To a solution of Compound 139 (128 mg, 0.301 mmol) and NH₄OAc (42 mg,0.545 mmol) in DMF (4 mL) were added HATU (198 mg, 0.520 mmol) and DIPEA(0.52 mL, 3.00 mmol). The reaction mixture was stirred at RT overnight,cooled to 0° C., quenched with water and extracted with DCM. The organicextracts were dried over Na₂SO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂, 0-80% MeOH/DCM) to give Compound140 as an off-white solid (99.5 mg). Yield 78%. ¹H NMR (400 MHz,DMSO-d₆) δ: 11.65 (d, J=2.2 Hz, 1H), 10.78 (s, 1H), 8.86 (d, J=1.3 Hz,1H), 8.22 (dd, J=8.6, 1.8 Hz, 1H), 8.16 (dd, J=7.9, 0.7 Hz, 1H),8.04-8.12 (m, 3H), 7.97-8.03 (m, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.52 (d,J=8.8 Hz, 1H), 7.44 (br. s., 1H), 6.89 (br. s., 1H). LC/MS: m/z=425[M+H]⁺ (Calc: 424).

In a similar manner, the following compounds were prepared:

(S)-2-(5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamido)pentanediamide(Compound 141): ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (d, J=2.4 Hz, 1H),10.78 (s, 1H), 8.87 (d, J=1.3 Hz, 1H), 8.22 (dd, J=8.7, 1.7 Hz, 1H),8.12-8.17 (m, 2H), 8.09 (d, J=9.0 Hz, 2H), 8.04-8.07 (m, 1H), 7.97-8.01(m, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6Hz, 1H), 7.33 (s, 1H), 7.26 (br. s., 1H), 6.98 (s, 1H), 6.72 (br. s.,1H), 4.36 (td, J=8.3, 5.2 Hz, 1H), 2.08-2.20 (m, 2H), 1.91-2.03 (m, 1H),1.79-1.90 (m, 1H). LC/MS: m/z=553 [M+H]⁺ (Calc: 552);

5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide(Compound 142): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.88 (d, J=1.1 Hz, 1H),8.02 (dd, J=6.9, 2.1 Hz, 1H), 7.98 (s, 1H), 7.87-7.96 (m, 3H), 7.55 (d,J=8.1 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 5.51 (s,2H). LC/MS: m/z=439 [M+H]⁺ (Calc: 438); and

(S)—N-(1-amino-1-oxopropan-2-yl)-5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide(Compound 143): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.93 (d, J=1.1 Hz, 1H),8.00-8.05 (m, 2H), 7.86-7.95 (m, 3H), 7.54 (d, J=8.1 Hz, 2H), 7.40 (d,J=8.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 5.50 (s, 2H), 4.55 (q, J=7.3 Hz,1H), 1.37-1.45 (m, 3H). LC/MS: m/z=510 [M+H]⁺ (Calc: 509).

Example 18 Synthesis of TFA salt of(S)-6-(3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide(Compound 144)

Compound 9 (25 mg, 0.247 mmol) was added to a solution of Compound 70(104.6 mg, 0.247 mmol) in DCE (2 mL) at 0° C. The mixture was stirredfor 30 min, AcOH (0.042 mL, 0.740 mmol) was added and the mixturestirred for an additional 10 min at 0° C. NaBH(OAc)₃ (105 mg, 0.493mmol) was added and the reaction mixture stirred at RT overnight. Waterwas added and the mixture extracted with DCM. The organic extracts werewashed with water, dried over MgSO₄ and concentrated. The residue waspurified by reverse-phase prep HPLC (C18, 0-60% 0.1% TFA in ACN/0.1% TFAin water) to give TFA salt of Compound 144 as an off-white solid (64.5mg). Yield 42%. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (br. s., 1H), 8.71 (d,J=0.9 Hz, 1H), 8.27-8.37 (m, 2H), 8.08-8.15 (m, 2H), 7.99 (t, J=7.7 Hz,1H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J=8.1 Hz, 3H), 7.53(d, J=8.6 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 5.59 (s, 2H), 4.57-4.67 (m,1H), 4.42-4.51 (m, 1H), 3.95-4.05 (m, 1H), 3.14-3.29 (m, 2H), 2.34-2.41(m, 1H), 1.99-2.12 (m, 1H). LC/MS: m/z=530 [M+Na]⁺ (Calc: 507).

In a similar manner, TFA salt of(S)-6-(1-(cyclohexylmethyl)-3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1H-indol-5-yl)picolinamide(Compound 145) was prepared:

¹H NMR (400 MHz, DMSO-d₆) δ: 9.21 (br. s., 1H), 8.68 (s, 1H), 8.26-8.37(m, 2H), 8.12 (d, J=7.7 Hz, 1H), 8.09 (dd, J=8.7, 1.4 Hz, 1H), 7.98 (t,J=7.7 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.52 (s, 1H), 4.38-4.64 (m, 2H), 4.03 (d, J=7.0 Hz, 2H),3.97 (br. s., 1H), 3.13-3.23 (m, 2H), 2.33-2.41 (m, 1H), 1.99-2.13 (m,1H), 1.73 (td, J=7.2, 3.5 Hz, 1H), 1.44-1.66 (m, 5H), 0.90-1.16 (m, 5H).LC/MS: m/z=468 [M+Na]⁺ (Calc: 445).

Example 19 Synthesis of TFA salt of(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-1H-indol-5-yl)pyridin-2-yl)propanamide(Compound 150)

A solution of Compound 146 (200 mg, 0.719 mmol) in THF (2 mL) was addeddropwise to a mixture of ethyl 2-(diethoxyphosphoryl)acetate (Compound147) (177 mg, 0.790 mmol) and NaH (63 mg, 1.581 mmol, 60% dispersion inoil) in THF (2 mL) at 0° C. The mixture was stirred at RT for 1 h,quenched with water and extracted with DCM. The organic extracts weredried over MgSO₄, concentrated and the residue purified by flashchromatography (SiO₂, 0-100% EtOAc/hexanes) to give Compound 148 as awhite solid (117.6 mg). Yield 47%. LC/MS: m/z=349 [M+H]⁺ (Calc: 348).

A suspension of Compound 148 (99.9 mg, 0.287 mmol) and AD-mix alpha (410mg, 1.36 g/mmol, Sigma-Aldrich) in 1:1 t-BuOH/water (4 mL) was stirredat RT overnight. The reaction was quenched by the addition of Na₂SO₃(400 mg), water was added and the mixture extracted with DCM. Theorganic extracts were washed with water, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography (SiO₂,0-50%, DCM/MeOH) to give Compound 149 as a white solid (99.8 mg). Yield91%. LC/MS: m/z=383 [M+H]⁺ (Calc: 382).

A solution of Compound 149 (99.8 mg, 0.261 mmol) in 7M NH₃ in MeOH (3mL) was heated to 45° C. overnight. The mixture was concentrated and theresidue purified by by reverse-phase prep HPLC (C18, 0-60% 0.1% TFA inACN/0.1% TFA in water) to give to give Compound 150 TFA salt as a yellowpowder (95.1 mg). Yield 78%. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.32 (t, J=7.9Hz, 1H), 8.02-8.15 (m, 2H), 7.81 (d, J=7.5 Hz, 1H), 7.60-7.68 (m, 1H),7.54-7.60 (m, 1H), 7.29 (d, J=3.1 Hz, 1H), 6.56 (d, J=3.1 Hz, 1H), 5.35(d, J=2.6 Hz, 1H), 4.38 (br. s., 1H), 3.96 (d, J=7.3 Hz, 2H), 2.05-2.19(m, 1H), 0.83 (d, J=6.8 Hz, 6H). LC/MS: m/z=354 [1\4+H]⁺ (Calc: 353).

In a similar manner, the following compounds were prepared:

(2R,3S)-2,3-dihydroxy-3-(6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)pyridin-2-yl)propanamide(Compound 151): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.23-8.30 (m, 1H), 8.15 (d,J=1.5 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.60 (dd,J=8.6, 1.8 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.41(d, J=3.3 Hz, 1H), 7.21 (d, J=7.9 Hz, 2H), 6.65 (d, J=3.1 Hz, 1H), 5.48(s, 2H), 5.31 (d, J=2.9 Hz, 1H), 4.38 (d, J=3.1 Hz, 1H). LC/MS: m/z=456[M+H]⁺ (Calc: 455);

(2R,3S)-3-(6-(1-(cyclohexylmethyl)-1H-indol-5-yl)pyridin-2-yl)-2,3-dihydroxypropanamide(Compound 152): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.34 (t, J=8.0 Hz, 1H),8.11 (d, J=1.5 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H),7.59-7.66 (m, 1H), 7.53-7.59 (m, 1H), 7.24-7.32 (m, 1H), 6.56 (d, J=3.1Hz, 1H), 5.36 (d, J=3.1 Hz, 1H), 4.37 (d, J=3.1 Hz, 1H), 3.99 (d, J=7.3Hz, 2H), 1.73-1.86 (m, 1H), 1.44-1.68 (m, 5H), 0.89-1.21 (m, 5H). LC/MS:m/z=394 [M+H]⁺ (Calc: 393);

(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-1H-indol-5-yl)pyridin-2-yl)propanamide(Compound 153): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.32 (t, J=1.0 Hz, 1H),8.12 (d, J=1.5 Hz, 1H), 8.08 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.63 (d,J=1.8 Hz, 1H), 7.54-7.60 (m, 1H), 7.30 (d, J=3.2 Hz, 1H), 6.57 (d, J=3.0Hz, 1H), 5.34 (d, J=3.0 Hz, 1H), 4.37 (d, J=3.1 Hz, 1H), 3.97 (d, J=7.4Hz, 2H), 2.06-2.21 (m, 1H), 0.84 (d, J=6.7 Hz, 6H). LC/MS: m/z=354[M+H]⁺ (Calc: 353);

(2R,3S)-3-(6-(1-(cyclopropylmethyl)-1H-indol-5-yl)pyridin-2-yl)-2,3-dihydroxypropanamide(Compound 154): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.26-8.31 (m, 1H), 8.12 (s,1H), 8.04 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.63-7.68 (m, 1H),7.56-7.61 (m, 1H), 7.38 (d, J=3.2 Hz, 1H), 6.56 (d, J=3.2 Hz, 1H), 5.33(d, J=2.9 Hz, 1H), 4.38 (d, J=3.0 Hz, 1H), 4.03 (d, J=6.9 Hz, 2H),1.16-1.27 (m, 1H), 0.48-0.55 (m, 2H), 0.30-0.36 (m, 2H). LC/MS: m/z=352[M+H]⁺ (Calc: 351); and

(2R,3S)-2,3-dihydroxy-3-(6-(1-isobutyl-1H-indazol-5-yl)pyridin-2-yl)propanamide(Compound 155): ¹H NMR (400 MHz, MeOH-d₄) δ: 8.34 (s, 1H), 8.07-8.16 (m,2H), 7.91-8.00 (m, 2H), 7.69-7.74 (m, 1H), 7.67 (d, J=8.9 Hz, 1H), 5.26(d, J=2.3 Hz, 1H), 4.46 (d, J=2.6 Hz, 1H), 4.19 (d, J=7.3 Hz, 2H), 2.24(dquin, J=13.7, 6.8 Hz, 1H), 0.84 (d, J=6.7 Hz, 6H). LC/MS: m/z=355[M+H]⁺ (Calc: 354).

Further, in a similar manner as those set forth in the foregoingexamples, Compound 156, i.e.,2-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)thiazole-4-carboxamide,was prepared: LC/MS: m/z=402.0 [M+H]⁺ (Calc: 401.1).

In the foregoing EXAMPLES the following abbreviations are used:

ACN Acetonitrile AcOH acetic acid aq. aqueous atm atmosphere(s) Boctert-butoxycarbonyl ° C. degrees Celsius conc. concentrated DCE1,2-dichloroethane DCM dichloromethane DIPEA diisopropylethylamine DME1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide Et₂Odiethyl ether EtOAc ethyl acetate EtOH ethanol h hour(s) HATU2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HPLC high pressure liquid chromatography i-PrOHiso-propanol MeOH methanol min minute(s) NBS N-bromosuccinimide NMPN-methyl-2-pyrrolidone Pd/C palladium on carbon Pd(dppf)Cl₂[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridePd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium(II) dichloridePd(P(o-tol)₃)₂Cl₂ bis[tris(2-methylphenyl)phosphine]palladium(II)dichloride PPh₃ triphenylphosphine psi pounds per square inch RT roomtemperature satd. saturated t-BuOH tert-butyl alcohol TEA triethylamineTFA trifluoroacetic acid THF tetrahydrofuran

Example 20

Representative Compounds of the Invention have been tested in the FLIPR®or FLIPR^(TETRA)® assay and/or EP assays for sodium channel blockingactivity, which is described in detail above. Representative values arepresented in TABLE 3.

TABLE 3 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7 Activity (μM) Na_(v)1.7 Activity (μM) Compound # FLIPR assayIC₅₀ EP assay K_(i) 29 >20 32 0.233 ± 0.035 33 >20 35 >20 36 >20 37 >2041 0.514 ± 0.054 0.322 ± 0.113 42 2.025 ± 0.146 44 1.720 ± 0.156 1.544 ±0.446 45 7.205 ± 0.562 47 4.189 ± 0.862 50 >20 51 3.514 ± 0.733 56 0.230± 0.026 57 0.658 ± 0.078 58 0.237 ± 0.062 59 0.927 ± 0.050 61 0.801 ±0.052 62 >20 63 1.117 ± 0.182 64 >20 65 >20 66 5.548 ± 0.376 67 0.308 ±0.078 68 10-20 75 3.034 ± 0.837 76 0.167 ± 0.020 77 2.699 ± 0.524 781.828 ± 0.459 1.279 ± 0.480 79 >20 80 >20 81 0.782 ± 0.044 83 0.180 ±0.031 84 >20 85 1.211 ± 0.242 86 >20 87 >20 88 4.886 ± 0.388 105 0.897 ±0.114 0.700 ± 0.049 106 1.332 ± 0.164 0.286 ± 0.027 107 1.091 ± 0.0770.534 ± 0.032 108 4.680 ± 0.412 109 0.177 ± 0.005 110 3.440 ± 0.712 1110.716 ± 0.073 112 4.117 ± 0.525 113 4.430 ± 0.541 119 5.089 ± 0.356 1201.910 ± 0.458 2.032 ± 0.608 121 2.368 ± 0.364 122 1.744 ± 0.214 1231.515 ± 0.152 1.025 ± 0.368 124 4.921 ± 0.700 125 >20 126 5.907 ± 0.536129 10-20 130 >20 131 >20 138 3.663 ± 2.403 139 >20 140 >20 141 >20142 >20 143 >20 144 2.543 ± 0.181 145 10-20 150 1.375 ± 0.146 0.678 ±0.172 151 0.773 ± 0.090 152 0.402 ± 0.032 153 2.621 ± 0.071 154 10~2027.160 ± 8.195 155 >20 10.633 ± 3.898 156 0.173 ± 0.018

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the disclosure or anyembodiment thereof.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference in their entirety.

What is claimed is:
 1. A compound of Formula IV:

wherein: X is NR^(4a), O, and S; Y is CR^(3a); and Z is CR^(3b); R^(4a)is selected from the group consisting of hydrogen, alkyl, cycloalkyl,hydroxyalkyl, optionally-substituted (cycloalkyl)alkyl,optionally-substituted (heterocyclo)alkyl, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, optionally-substituted aralkyl,optionally-substituted (heteroaryl)alkyl, optionally substituted aryl,—COR^(11a), and —SO₂R^(11b); R^(3a) is selected from the groupconsisting of hydrogen, alkyl, optionally substituted cycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;R^(3b) is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,optionally substituted aryl, (heterocycloamino)alkyl, —CO₂H, and—C(═O)NR^(12a)R^(12b); R^(11a) is selected from the group consisting ofalkyl, optionally substituted cycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; R^(11b) is selected from thegroup consisting of alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, amino, alkylamino,dialkylamino, and heterocyclo; R^(12a) is selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, heterocyclo, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted (cycloalkyl)alkyl,optionally substituted (heterocyclo)alkyl, optionally substituted(heteroaryl)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl, hydroxyalkyl, andheteroalkyl; R^(12b) is selected from the group consisting of hydrogenand alkyl; or R^(12a) and R^(12b) taken together with the nitrogen atomto which they are attached form an optionally substituted 3- to8-membered heterocyclo group; R^(1e) and R^(1f) are hydrogen; W₄ is CH;G is —C(═O)E; R⁵ is selected from the group consisting of hydrogen,halo, hydroxy, alkyl, hydroxyalkyl, cyano, heterocyclo, and —X¹—R⁷; X¹is selected from the group consisting of —O—, —NR^(8a)—, and—(CH₂)_(t)—Y¹—; Y¹ is selected from the group consisting of —O— and—NR^(8b)—; t is 1 or 2; R⁷ is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl,

R^(8a) is selected from the group consisting of hydrogen and alkyl;R^(8b) is selected from the group consisting of hydrogen and alkyl; orR^(8b) and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo; R⁹is selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl; and R^(10a) and R^(10b) are independently selected fromthe group consisting of hydrogen and alkyl; or R^(10a) and R^(10b) takentogether with the nitrogen atom to which they are attached form a 3- to8-membered optionally substituted heterocyclo; E is —NR¹R²; R¹ isselected from the group consisting of hydrogen, alkyl, cycloalkyl,optionally substituted aryl, heteroaryl, and optionally substituted(cycloalkyl)alkyl; and R² is hydrogen; or a pharmaceutically acceptablesalt or solvate thereof.
 2. A compound selected from the groupconsisting of: 6-(1-methyl-3-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)picolinamide; 6-(1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)picolinamide;6-(1-(2-(diethylamino)ethyl)-3-(4-fluorophenyl)-1H-indol-6-yl)picolinamide;6-(1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;6-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indol-5-yl)picolinamide;6-(1H-indol-5-yl)picolinamide;6-(1-methyl-1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;N-cyclohexyl-6-(1H-indol-5-yl)picolinamide;(S)-6-(1H-indol-5-yl)-4-((2-oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)-phenyl)picolinamide;6-(1-(cyclohexylmethyl)-1H-indol-5-yl)picolinamide;6-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamide;5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxylicacid;(S)-2-(5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamido)pentanediamide;5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;(S)—N-(1-amino-1-oxopropan-2-yl)-5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;N-(cyclohexylmethyl)-6-(1H-indol-5-yl)picolinamide;6-(1-(4-fluorobenzyl)-1H-indol-5-yl)picolinamide;N-cyclopentyl-6-(1H-indol-5-yl)picolinamide;6-(1-(2-cyclohexylethyl)-1H-indol-5-yl)picolinamide;6-(1H-indol-5-yl)-N-(1H-tetrazol-5-yl)picolinamide;6-(1-((2-methylthiazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;6-(1-isobutyl-1H-indol-5-yl)picolinamide; 6-(1-(4-methylbenzyl)-1H-indol-5-yl)picolinamide;6-(1-(pyridin-4-ylmethyl)-1H-indol-5-yl)picolinamide;6-(1-(cyclohexylsulfonyl)-1H-indol-5-yl)picolinamide;6-(1-(2-morpholinoethyl)-1H-indol-5-yl)picolinamide;(S)-6-(3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;6-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;(S)-6-(1-(cyclohexylmethyl)-3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1H-indol-5-yl)picolinamide;(R)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;(S)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;(S)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide;(R)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide; anda pharmaceutically acceptable salt or solvate thereof.
 3. Apharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 4. A method for treating pain in amammal, comprising administering an effective amount of a compound asclaimed in claim 1, or a pharmaceutically acceptable salt or solvatethereof, to a mammal in need of such treatment.
 5. The method of claim4, wherein said pain is selected from the group consisting of chronicpain, inflammatory pain, neuropathic pain, acute pain, and surgicalpain.
 6. A method of modulating Nav1.7 sodium channels in a mammal,comprising administering to the mammal at least one compound as claimedin claim 1, or a pharmaceutically acceptable salt or solvate thereof. 7.A compound as claimed in claim 1, or a pharmaceutically acceptable saltor solvate thereof, wherein the compound is ³H, ¹¹C, or ¹⁴Cradiolabeled.
 8. A pharmaceutical composition comprising the compound ofclaim 2, or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.